U.S. patent application number 12/635907 was filed with the patent office on 2010-06-17 for novel benzodioxane and benzoxazine derivatives useful as cc chemokine receptor ligands.
Invention is credited to Sumit Kumar Karak, Uttam KHAMRAI, Matthew Ronsheim.
Application Number | 20100152160 12/635907 |
Document ID | / |
Family ID | 42241251 |
Filed Date | 2010-06-17 |
United States Patent
Application |
20100152160 |
Kind Code |
A1 |
KHAMRAI; Uttam ; et
al. |
June 17, 2010 |
NOVEL BENZODIOXANE AND BENZOXAZINE DERIVATIVES USEFUL AS CC
CHEMOKINE RECEPTOR LIGANDS
Abstract
The present invention relates to benzodioxane and benzoxazine
derivatives that act as ligands for CC chemokine receptors, such as
CCR1. The invention also relates to methods of preparing the
compounds, compositions containing the compounds, and to methods of
treatment using the compounds.
Inventors: |
KHAMRAI; Uttam; (Kolkata,
IN) ; Ronsheim; Matthew; (Port Jefferson, NY)
; Karak; Sumit Kumar; (Kolkata, IN) |
Correspondence
Address: |
Forest Laboratories, Inc.;Attn: Charles S. Ryan
48 Mall Drive
Commack
NY
11725
US
|
Family ID: |
42241251 |
Appl. No.: |
12/635907 |
Filed: |
December 11, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61121937 |
Dec 12, 2008 |
|
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|
Current U.S.
Class: |
514/210.21 ;
514/211.15; 514/218; 514/230.5; 514/254.11; 540/544; 540/575;
544/105; 544/377 |
Current CPC
Class: |
C07D 413/06 20130101;
A61P 37/00 20180101; A61P 3/00 20180101; A61P 3/10 20180101; C07D
417/14 20130101; A61P 29/00 20180101; C07D 413/14 20130101; C07D
498/02 20130101 |
Class at
Publication: |
514/210.21 ;
544/377; 514/254.11; 514/218; 540/575; 544/105; 514/230.5;
514/211.15; 540/544 |
International
Class: |
C07D 413/06 20060101
C07D413/06; C07D 405/06 20060101 C07D405/06; A61K 31/496 20060101
A61K031/496; A61K 31/551 20060101 A61K031/551; C07D 413/02 20060101
C07D413/02; A61K 31/538 20060101 A61K031/538; A61K 31/553 20060101
A61K031/553; A61P 29/00 20060101 A61P029/00; A61P 37/00 20060101
A61P037/00; A61P 3/00 20060101 A61P003/00; A61P 3/10 20060101
A61P003/10 |
Claims
1. A compound having the chemical structure: ##STR00191## wherein
X.sup.2 is 0 or --NR.sup.17, where R.sup.17 is hydrogen, alkyl,
acyl, heteroaryl, --C(O)--CF.sub.3, cyano, alkylsulfinyl,
alkylsulfonyl, amino, --C(O)-aminoalkyl, -alkyleneamino,
-alkylene-OH, -alkylene-C(O)NR.sup.eR.sup.f, or
-alkylene-NR.sup.eR.sup.f, where R.sup.e and R.sup.f are each,
independently, hydrogen or alkyl; y.sup.2 is --C(O)--,
--CH.sub.2C(O)--, --CH.sub.2CH.sub.2-- or --CH.sub.2--; M is
selected from the group consisting of --C--, --N--, and --O--;
Z.sup.1 is selected from the group consisting of hydrogen, aryl,
heteroaryl, heterocycle, arylalkyl, heteroarylalkyl or
heterocyclealkyl; Z.sup.3 is --C(O)-aryl, --C(O)-heteoraryl,
--C(O)-arylalkyl, or --C(O)-heteroarylalkyl, arylalkyl or
heteroarylalkyl; R.sup.18, R.sup.19, R.sup.20 and R.sup.21 are
each, independently, hydrogen, halogen, hydroxy, cyano, nitro,
amino, alkylamino, dialkylamino, carboxyl, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylamino, heteroarylalkyl, heterocycle, heterocyclealkyl,
aroyl, acyl, alkoxy, aryloxy, cycloalkyloxy, cycloalkylalkyloxy,
arylalkyloxy, heteroarylalkyloxy, alkythio, arylthio,
alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl,
heteroaryloxycarbonyl --O-alkylene-CO.sub.2H,
--O-alkylene-C(O)NR.sup.xR.sup.y or NR.sup.xC(O)-alkyl, in which
R.sup.x and R.sup.y are each, independently, hydrogen or alkyl;
R.sup.22 and R.sup.23 are each hydrogen, or R.sup.22 and R.sup.23,
together with the carbon atom to which they are attached, form a
--C(O)-group; R.sup.24 and R.sup.25 are each, independently,
hydrogen, alkyl or arylalkyl; V is alkyl; w is 0, 1 or 2; q is 0 or
1; R.sup.26 is hydrogen, hydroxyl, --CO.sub.2Et, cyano, heteroaryl,
-alkylene-OH, or -alkylene-NH.sub.2; wherein when R.sup.26 is
hydrogen, then X.sup.2 is --NR.sup.17-- and Z.sup.3 is --C(O)-aryl,
--C(O)-heteoraryl, --C(O)-arylalkyl, or --C(O)-heteroarylalkyl; and
when R.sup.26 is hydroxyl, --CO.sub.2Et, cyano, heteroaryl,
-alkylene-OH, or -alkylene-NH.sub.2, then Z.sup.3 is arylalkyl or
heteroarylalkyl; R.sup.35 is hydrogen or alkyl; provided, however,
that when R.sup.26 is present, then M is --C--; provided, however,
that when Z.sup.3 is present, then M is --C-- or --N--; provided,
however, than when M is --O--, then Z.sup.1 is arylalkyl; provided,
however, than when w is 1, X.sup.2 is --O--, and M is --N--, then
Z.sup.3 is optionally substituted 4-fluorobenzyl, wherein, when
present, any aryl, heteroaryl or heterocycle group may optionally
be substituted by halogen, hydroxy, cyano, nitro, amino,
alkylamino, dialkylamino, arylamino, diarylamino, amido, carboxyl,
alkyl, halogenated alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycle, heterocyclealkyl, aroyl, acyl, alkoxy, aryloxy,
heteroaryloxy, cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy,
heteroarylalkyloxy, alkythio, arylthio, alkylsulfinyl,
alkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroarylsulfinyl,
heteroarylsulfonyl, alkoxycarbonyl, aryloxycarbonyl,
heteroaryloxycarbonyl, and combinations thereof; and
pharmaceutically acceptable salts or solvates or N-oxides thereof,
or solvates of pharmaceutically acceptable salts thereof, or
pharmaceutically acceptable salts or solvates of N-oxides thereof,
prodrugs and isomers thereof, with the proviso that said compound
is not:
[4-[(2-chloro-4-fluorophenyl)methyl]-1-piperazinyl](2,3-dihydro-1,4-benzo-
dioxin-2-yl)-methanone,
1-[2,3-dihydro-2-[[4-(1-naphthalenylmethyl)-1-piperazinyl]carbonyl]-4H-1,-
4-benzoxazin-4-yl]-ethanone,
1-[2,3-dihydro-2-[[4-[[4-(trifluoromethyl)phenyl]methyl]-1-piperazinyl]ca-
rbonyl]4H-1,4-benzoxazin-4-yl]-ethanone,
[4-(ethylsulfonyl)-3,4-dihydro-2H-1,4-benzoxazin-2-yl][4-(phenylmethyl)-1-
-piperazinyl]-methanone,
2-[2-oxo-2-[4-(phenylmethyl)-1-piperazinyl]ethyl]-2H-1,4,-benzoxazin-3(4H-
)-one, or
1-2[[hexahydro-4-[(4-methoxyphenyl)methyl]-1H-1,4-diazepin-1-yl]-
carbonyl]-2,3-dihydro-4H-1,4-benzoxazin-4-yl]-ethanone,
1-[2-[(4-benzoyl-1-piperidinyl)carbonyl]-2,3-dihydro-4H-1,4-benzoxazin-4--
yl]-ethanone,
1-[2-[(4-(4-hydroxy)benzoyl-1-piperidinyl)carbonyl]-2,3-dihydro-4H-1,4-be-
nzoxazin-4-yl]-ethanone,
1-[2-(2,3-dihydro-1,4-benzodioxin-2-yl)ethyl]-4-(4-methylphenyl)-4-piperi-
dinol, or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, selected from:
(6-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[(R)-4-(4-fluoro-benzyl)-2-m-
ethyl-piperazin-1-yl]-methanone,
(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-[(R)-4-(4-fluoro-benzyl)-2-methyl-pip-
erazin-1-yl]-methanone,
(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-[4-(4-fluoro-benzyl)-piperazin-1-yl]--
methanone,
(6-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[4-(4-fluoro-benzy-
l)-piperazin-1-yl]-methanone,
(6-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[4-(4-fluoro-benzyl)-[1,4]di-
azepan-1-yl]-methanone,
(6,7-Dichloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[(R)-4-(4-fluoro-benzyl)-
-2-methyl-piperazin-1-yl]-methanone,
(6,7-Dichloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[4-(4-fluoro-benzyl)-[1,-
4]diazepan-1-yl]-methanone,
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[(R)-4-(4-fluoro-benzyl)--
2-methyl-piperazin-1-yl]-methanone,
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-benzyl)-pipe-
razin-1-yl]-methanone,
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-benzyl)-[1,4-
]diazepan-1-yl]-methanone,
6-Chloro-2-[4-(4-fluoro-benzyl)-[1,4]diazepane-1-carbonyl]-2,3-dihydro-be-
nzo[1,4]oxazine-4-carboxylic acid amide,
(6-Chloro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[(R)-4-(4-fluoro-
-benzyl)-2-methyl-piperazin-1-yl]-methanone,
(6-Chloro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-ben-
zyl)-[1,4]diazepan-1-yl]-methanone,
6-Chloro-2-[(R)-4-(4-fluoro-benzyl)-2-methyl-piperazine-1-carbonyl]-4H-be-
nzo[1,4]oxazin-3-one,
1-{6-Chloro-2-[4-(4-fluoro-benzyl)-piperazine-1-carbonyl]-2,3-dihydro-ben-
zo[1,4]oxazin-4-yl}-ethanone,
(6-Chloro-4-methanesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-f-
luoro-benzyl)-piperazin-1-yl]-methanone,
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[7-(4-fluoro-benzyl)-[1,4-
]oxazepan-4-yl]methanone,
1-{6-Chloro-2-[4-(4-fluoro-benzyl)-piperazine-1-carbonyl]-2,3-dihydro-ben-
zo[1,4]oxazin-4-yl}-2-dimethylamino-ethanone,
(6-Chloro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-ben-
zyl)-piperazin-1-yl]-methanone,
1-{6-Chloro-2-[4-(4-fluoro-benzyl)-piperazine-1-carbonyl]-2,3-dihydro-ben-
zo[1,4]oxazin-4-yl}-2-methylamino-ethanone,
2-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-1-[(R)-4-(4-fluoro-benz-
yl)-2-methyl-piperazin-1-yl]-ethanone,
2-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-1-[4-(4-fluoro-benzyl)--
[1,4]diazepan-1-yl]ethanone,
(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[(R)-4-(4-fluor-
o-benzyl)-2-methyl-piperazin-1-yl]-methanone,
(6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[(R)-4-
-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-methanone,
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[7-(4-fluoro-benzyl)-[1,4-
]oxazepan-4-yl]-methanone,
2-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-1-[7-(4-fluoro-benzyl)--
[1,4]oxazepan-4-yl]-ethanone,
2-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-1-[2-(4-fluoro-benzyl)--
[1,4]oxazepan-4-yl]-ethanone, and
6-Chloro-2-{2-[2-(4-fluoro-benzyl)-[1,4]oxazepan-4-yl]-ethyl}-3,4-dihydro-
-2H-benzo[1,4]oxazine,
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-benzoyl)-pip-
eridin-1-yl]-methanone,
1-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fluoro-benz-
yl)-piperidine-4-carbonitrile,
[1-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)-4-(4-fluoro-benz-
yl)-piperidin-4-yl]-methylamine,
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-f-
luoro-benzyl)-piperidine-4-carbonitrile,
4-(4-Chloro-benzyl)-1-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbon-
yl)-piperidine-4-carbonitrile,
[4-(4-Chloro-benzyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-(6-chloro-3,4-
-dihydro-2H-benzo[1,4]oxazin-2-yl)-methanone,
4-(4-Chloro-benzyl)-1-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethy-
l)-3,3-dimethyl-piperidin-4-ol,
1-(6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbony-
l)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-hydroxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-f-
luoro-benzyl)-piperidine-4-carbonitrile,
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dih-
ydro-2H-benzo[1,4]oxazin-7-yloxy}-acetic acid,
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dih-
ydro-2H-benzo[1,4]oxazin-7-yloxy}-acetamide,
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dih-
ydro-2H-benzo[1,4]oxazin-7-yloxy}-N,N-dimethyl-acetamide,
1-(6-Chloro-7-ethoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile,
1-[6-Chloro-4-(2-dimethylamino-acetyl)-7-methoxy-3,4-dihydro-2H-benzo[1,4-
]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(4-Acetyl-6-chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbony-
l)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-[4-(4-Chloro-benzyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-2-(6-chloro-
-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-ethanone,
4-(4-Chloro-benzyl)-1-[2-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)--
ethyl]-3,3-dimethyl-piperidin-4-ol,
1-[2-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-ethyl]-4-(4-fluoro-b-
enzyl)-3,3-dimethyl-piperidin-4-ol,
1-(6-Chloro-4-methanesulfonyl-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine--
2-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-metho-
xy-2,3-dihydro-benzo[1,4]oxazin-4-yl) -acetamide,
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
N-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dih-
ydro-2H-benzo[1,4]oxazin-7-yl) -acetamide,
4-(4-Fluoro-benzyl)-1-(7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbo-
nyl)-piperidine-4-carbonitrile,
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-methoxy--
2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid amide,
1-(7-Bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-flu-
oro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-8-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6,7-Dichloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fluoro--
benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-isopropoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(-
4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(4-Acetyl-6-chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-c-
arbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-dimet-
hylamino-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetamide,
1-(6-Chloro-7-dimethylamino-4-methanesulfonyl-3,4-dihydro-2H-benzo[1,4]ox-
azine-2-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-isopr-
opoxy-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetamide,
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-ethox-
y-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetamide,
1-(6-Chloro-7-ethoxy-4-methanesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-
-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-pyrrolidin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl-
)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(7-Azetidin-1-yl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-difluoromethoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl-
)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(7-Chloro-6-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-f-
luoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-diethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-morpholin-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-
-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-ph-
enoxy)-piperidin-1-yl]-methanone,
1-[6-Chloro-4-(2-hydroxy-ethyl)-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-
e-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-[6-Chloro-7-dimethylamino-4-(2-hydroxy-ethyl)-3,4-dihydro-2H-benzo[1,4]-
oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-dimethyl-
amino-2,3-dihydro-benzo[1,4]oxazine-4-carbonitrile,
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-methylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4--
(4-fluoro-benzyl)-piperidine-4-carbonitrile,
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-metho-
xy-2,3-dihydro-benzo[1,4]oxazin-4-yl}-N-methyl-acetamide,
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(6-f-
luoro-pyridin-3-ylmethyl)-piperidine-4-carbonitrile,
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-methoxy--
2,3-dihydro-benzo[1,4]oxazine-4-carbonitrile,
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-f-
luoro-benzyl)-piperidine-4-carboxylic acid ethyl ester,
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carboxylic acid ethyl ester,
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-pyri-
din-4-ylmethyl-piperidine-4-carbonitrile,
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-pyridin-4-ylmethyl-piperidine-4-carbonitrile,
(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-be-
nzyl)-4-hydroxymethyl-piperidin-1-yl]-methanone,
(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-flu-
oro-benzyl)-4-hydroxymethyl-piperidin-1-yl]-methanone,
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidine-4-carbonitrile,
1-[6-Chloro-7-dimethylamino-4-(2-dimethylamino-ethyl)-3,4-dihydro-2H-benz-
o[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-[6-Chloro-4-(2-dimethylamino-ethyl)-7-methoxy-3,4-dihydro-2H-benzo[1,4]-
oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-be-
nzyl)-4-imidazol-1-ylmethyl-piperidin-1-yl]-methanone,
1-(6-Chloro-7-ethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-flu-
oro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-[(4--
fluoro-phenyl)-hydroxy-methyl]-piperidine-4-carbonitrile,
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
3-(4-fluoro-benzyl)-pyrrolidine-3-carbonitrile,
{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dihyd-
ro-2H-benzo[1,4]oxazin-7-yl}-methyl-cyanamide,
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-[dif-
luoro-(4-fluoro-phenyl)-methyl]-piperidine-4-carbonitrile,
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-[difluoro-(4-fluoro-phenyl)-methyl]-piperidine-4-carbonitrile,
1-[6-Chloro-7-(1H-pyrazol-4-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbon-
yl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
6-Chloro-7-[methyl-(2H-tetrazol-5-yl)-amino]-3,4-dihydro-2H-benzo[1,4]oxa-
zine-2-carboxylic acid
[3-cyano-3-(4-fluoro-benzyl)-pentyl]-methyl-amide,
1-[6-Chloro-7-(2H-tetrazol-5-ylamino)-3,4-dihydro-2H-benzo[1,4]oxazine-2--
carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-[6-Chloro-7-dimethylamino-4-(2,2,2-trifluoro-acetyl)-3,4-dihydro-2H-ben-
zo[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-[6-Chloro-7-methoxy-4-(2,2,2-trifluoro-acetyl)-3,4-dihydro-2H-benzo[1,4-
]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-imidazol-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-[6-Chloro-7-methoxy-4-(2H-tetrazol-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazi-
ne-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
4-(4-Fluoro-benzyl)-1-(quinoxaline-2-carbonyl)-piperidine-4-carbonitrile,
4-(4-Fluoro-benzyl)-1-([1,2,4]triazolo[1,5-a]pyrimidine-2-carbonyl)-piper-
idine-4-carbonitrile,
4-(4-Fluoro-benzyl)-1-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-piperidine-4-
-carbonitrile
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,3-dihydr-
o-benzo[1,4]oxazine-4-carbonitrile,
1-[6-Chloro-4-(2H-tetrazol-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbo-
nyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-[6-Chloro-4-(1H-[1,2,4]triazol-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-
-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-pyrrol-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4--
(4-fluoro-benzyl)piperidine-4-carbonitrile,
1-[6-Chloro-7-methoxy-4-(1H-[1,2,4]triazol-3-yl)-3,4-dihydro-2H-benzo[1,4-
]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-[6-Chloro-8-(1H-pyrazol-4-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbon-
yl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-8-pyridin-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-8-thiophen-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-thiophen-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-pyridin-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-pyridin-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-[6-Chloro-7-(2-methyl-2H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-
-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-[6-Chloro-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-
-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-pyrazol-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-pyrimidin-5-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-
-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile, 1-(6-Chloro-7-hexa
deuterio
dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4--
fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-furan-2-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(-
4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-furan-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(-
4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-[6-Chloro-7-(4-methyl-imidazol-1-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-
-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-[6-Chloro-7-(3-methyl-pyrazol-1-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2--
carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-[1,2,4]triazol-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-[1,2,3]triazol-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-4-methyl-7-oxazol-5-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-car-
bonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-[6-Chloro-7-dimethylamino-4-(1H-[1,2,4]triazol-3-yl)-3,4-dihydro-2H-ben-
zo[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-[6-Chloro-7-(6-fluoro-pyridin-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2--
carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-[6-Chloro-7-(6-methoxy-pyridin-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-
-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-[6-Chloro-7-(2-methoxy-pyridin-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-
-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-2-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-climethylamino-2-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2--
carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-dimethyl-
amino-2,3-dihydro-benzo[1,4]oxazine-4-carbonitrile,
1-[6-Chloro-7-(2-methoxy-phenyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbo-
nyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-pyridin-2-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(7-Acetyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile,
1-(6-Chloro-7-oxazol-5-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4--
(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(4-Chloro-2-methyl-3,6,7,8-tetrahydro-9-oxa-1,3,6-triaza-cyclopenta[a]n-
aphthalene-8-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
1-(4-Chloro-3,6,7,8-tetrahydro-9-oxa-1,3,6triazacyclopenta[a]naphthalene--
8-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dihydr-
o-2H-benzo[1,4]oxazine-7-carboxylic acid methylamide,
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dihydr-
o-2H-benzo[1,4]oxazine-7-carbonitrile,
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dihydr-
o-2H-benzo[1,4]oxazine-7-carboxylic acid dimethylamide, and
1-[6-Chloro-7-(2-methyl-thiazol-4-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2--
carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile, and
pharmaceutically acceptable salts thereof, solvates thereof, and
solvates of pharmaceutically acceptable salts thereof, wherein if
the compound exhibits chirality it can be in the form of a mixture
of enantiomers such as a racemate or a mixture of diastereomers, or
can be in the form of a single enantiomer or a single
diastereomer.
3. A compound selected from:
6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
[1-(4-fluoro-benzyl)-piperidin-4-yl]-amide,
N-[1-(4-Chloro-benzyl)-piperidin-4-yl]-2-(6-chloro-3,4-dihydro-2H-benzo[1-
,4]oxazin-2-yl)-acetamide,
[1-(4-Chloro-benzyl)-piperidin-4-yl]-[2-(6-chloro-3,4-dihydro-2H-benzo[1,-
4]oxazin-2-yl)-ethyl]-amine,
6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid [1-(4-fluoro-benzyl)-piperidin-4-yl]-amide,
6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid [1-(4-fluoro-benzyl)-4-hydroxy-piperidin-4-ylmethyl]-amide,
and
6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid [1-(4-fluoro-benzyl)-4-hydroxy-piperidin-4-ylmethyl]-amide,
and pharmaceutically acceptable salts thereof, solvates thereof,
and solvates of pharmaceutically acceptable salts thereof, wherein
if the compound exhibits chirality it can be in the form of a
mixture of enantiomers such as a racemate or a mixture of
diastereomers, or can be in the form of a single enantiomer or a
single diastereomer.
4. A pharmaceutical composition comprising a compound according to
claim 1 and a pharmaceutical acceptable carrier.
5. A method for treating a condition that responds to a CC
chemokine receptor ligand comprising administering to a patient in
need thereof an effective amount of a composition according to
claim 4.
6. The method of claim 5, wherein the CC chemokine receptor ligand
is a CCR1 antagonist.
7. The method according to claim 5, wherein the condition is
selected from a group consisting of inflammatory disorder,
autoimmune diseases, diabetes, obesity, and metabolic syndrome.
8. The method according to claim 7, wherein the condition is
inflammatory disorder.
9. The method according to claim 7, wherein the condition is
autoimmune diseases.
10. The method according to claim 7, wherein the condition is
diabetes.
11. The method according to claim 7, wherein the condition is
obesity.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to benzodioxane and
benzoxazine derivatives that act as ligands for CC chemokine
receptors, such as CCR1. The invention also relates to methods of
preparing the compounds, compositions containing the compounds, and
to methods of treatment using the compounds.
BACKGROUND OF THE INVENTION
[0002] The selective accumulation and activation of leukocytes in
inflamed tissues contributes to the pathogenesis of inflammatory
and autoimmune diseases. Chemokines and their receptors, which
belong to a family of seven transmembrane G-protein coupled
receptors are involved in the selective accumulation and activation
of leukocytes in inflamed tissues, and in the pathogenesis of
inflammatory and autoimmune diseases. One such receptor is CCR1
which is a receptor for CC chemokines such as RANTES (regulated on
activation normal Tcell expressed), MIP-1.alpha. (macrophage
inflammatory protein) MPIF-1/CK.beta.8 and Leukotactin chemokine,
among others.
[0003] The receptor CCR1 and its chemokine ligands represent
significant therapeutic targets (see, e.g., Saeki, et al., Current
Pharmaceutical Design, 9, 1201-1208, 2003) since they have been
implicated in, for example, rheumatoid arthritis, transplant
rejection (see, e.g., DeVries, et al., Semin. Immunol., 11(2),
95-104, 1999), and multiple sclerosis (see, e.g., Fischer, et al.,
J. Neuroimmunol., 110(1-2), 195-208, 2000, Izikson, et al., J Exp.
Med., 192(7), 1075-1080, 2000, and Rottman, et al., Eur. J.
Immunol., 30(8), 2372-2377, 2000). In vivo studies on mice indicate
that CCR1-mediated leukocyte recruitment is important for
interstitial inflammation in the kidney and that CCR1 blockade late
in renal disease can halt disease progression and improve renal
function (see, e.g., NAME, J. Am. Soc. Nephrol., 15, 1504-1513,
2004). Further, an animal model of neutrophil recruitment in
response to MIP-1.alpha. demonstrates the positive biological and
pharmacodynamic activity of CCR1 antagonists (see, e.g., U.S.
2005/0288319).
[0004] There is therefore an ongoing need to develop new compounds
that can be used in the treatment of diseases mediated by CCR1
signaling.
SUMMARY OF THE INVENTION
[0005] The present invention relates to benzodioxane and
benzoxazine derivatives that act as ligands for CC chemokine
receptors, such as CCR1. The invention also relates to methods of
preparing the compounds, compositions containing the compounds, and
to methods of treatment using the compounds.
DETAILED DESCRIPTION OF THE INVENTION
[0006] In one aspect, the present invention includes compounds
having the chemical structure:
##STR00001##
[0007] wherein
[0008] X.sup.2 is O or --NR.sup.17, where R.sup.17 is hydrogen,
alkyl, acyl, heteroaryl, --C(O)--CF.sub.3, cyano, alkylsulfinyl,
alkylsulfonyl, amido, --C(O)-aminoalkyl, -alkyleneamino,
-alkylene-OH, -alkylene-C(O)NR.sup.eR.sup.f, or
-alkylene-NR.sup.eR.sup.f, where R.sup.e and R.sup.f are each,
independently, hydrogen or alkyl;
[0009] Y.sup.2 is --C(O)--, --CH.sub.2C(O)--, --CH.sub.2CH.sub.2--
or --CH.sub.2--;
[0010] M is selected from the group consisting of --C--, --N--, and
--O--;
[0011] Z.sup.1 is selected from the group consisting of hydrogen,
aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl or
heterocyclealkyl;
[0012] Z.sup.3 is --C(O)-aryl, --C(O)-heteoraryl, --C(O)-arylalkyl,
or --C(O)-heteroarylalkyl, arylalkyl or heteroarylalkyl;
[0013] R.sup.18, R.sup.19, R.sup.20 and a R.sup.21 are each,
independently, hydrogen, halogen, hydroxy, cyano, nitro, amino,
alkylamino, dialkylamino, carboxyl, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylamino, heteroarylalkyl, heterocycle, heterocyclealkyl,
aroyl, acyl, alkoxy, aryloxy, cycloalkyloxy, cycloalkylalkyloxy,
arylalkyloxy, heteroarylalkyloxy, alkythio, arylthio,
alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl,
heteroaryloxycarbonyl --O-alkylene-CO.sub.2H,
--O-alkylene-C(O)NR.sup.xR.sup.y or NR.sup.xC(O)-alkyl, in which
R.sup.x and R.sup.y are each, independently, hydrogen or alkyl;
[0014] R.sup.22 and R.sup.23 are each hydrogen, or R.sup.22 and
R.sup.23, together with the carbon atom to which they are attached,
form a --C(O)-- group;
[0015] R.sup.24 and a R.sup.25 are each, independently, hydrogen,
alkyl or arylalkyl;
[0016] V is alkyl;
[0017] w is 0, 1 or 2;
[0018] q is 0 or 1;
[0019] R.sup.26 K is hydrogen, hydroxyl, --CO.sub.2Et, cyano,
heteroaryl, -alkylene-OH, or -alkylene-NH.sub.2; wherein
[0020] when R.sup.26 is hydrogen, then X.sup.2 is -NR.sup.17-- and
Z.sup.3 is --C(O)-aryl, --C(O)-heteoraryl, --C(O)-arylalkyl, or
--C(O)-heteroarylalkyl; and
[0021] when R.sup.26 is hydroxyl, --CO.sub.2Et, cyano, heteroaryl,
-alkylene-OH, or -alkylene-NH.sub.2, then Z.sup.3 is arylalkyl or
heteroarylalkyl;
[0022] R.sup.35 is hydrogen or alkyl;
[0023] provided, however, that when R.sup.26 is present, then M is
--C--;
[0024] provided, however, that when Z.sup.3 is present, then M is
--C-- or --N--;
[0025] provided, however, than when M is --O--, then Z.sup.1 is
arylalkyl;
[0026] provided, however, than when w is 1, X.sup.2 is --O--, and M
is --N--, then Z.sup.3 is optionally substituted
4-fluorobenzyl,
[0027] wherein, when present, any aryl, heteroaryl or heterocycle
group may optionally be substituted by halogen, hydroxy, cyano,
nitro, amino, alkylamino, dialkylamino, arylamino, diarylamino,
amido, carboxyl, alkyl, halogenated alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocycle, heterocyclealkyl, aroyl, acyl,
alkoxy, aryloxy, heteroaryloxy, cycloalkyloxy, cycloalkylalkyloxy,
arylalkyloxy, heteroarylalkyloxy, alkythio, arylthio,
alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl,
heteroarylsulfinyl, heteroarylsulfonyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, and combinations
thereof;
[0028] and pharmaceutically acceptable salts or solvates or
N-oxides thereof, or solvates of pharmaceutically acceptable salts
thereof, or pharmaceutically acceptable salts or solvates of
N-oxides thereof, prodrugs and isomers thereof,
[0029] with the proviso that said compound is not:
[0030]
[4-[(2-chloro-4-fluorophenypmethyl]-1-piperazinyl]-(2,3-dihydro-1,4-
-benzodioxin-2-yl)-methanone,
[0031]
1-[2,3-dihydro-2-[[4-(1-naphthalenylmethyl)-1-piperazinyl]carbonyl]-
-4H-1,4-benzoxazin-4-yl]-ethanone,
[0032]
1-[2,3-dihydro-2-[[4-[[4-(trifluoromethyl)phenyl]methyl]-1-piperazi-
nyl]carbonyl]4H-1,4-benzoxazin-4-yl]-ethanone,
[0033]
[4-(ethylsulfonyl)-3,4-dihydro-2H-1,4-benzoxazin-2-yl][4-(phenylmet-
hyl)-1-piperazinyl]-methanone,
[0034]
2-[2-oxo-2-[4-(phenylmethyl)-1-piperazinyl]ethyl]-2H-1,4,-benzoxazi-
n-3(4H)-one, or
[0035]
1-2[[hexahydro-4-[(4-methoxyphenyl)methyl]-1H-1,4-diazepin-1-yl]car-
bonyl]-2,3-dihydro-4H-1,4-benzoxazin-4-yl]-ethanone,
[0036]
1-[2-[(4-benzoyl-1-piperidinyl)carbonyl]-2,3-dihydro-4H-1,4-benzoxa-
zin-4-yl]-ethanone,
[0037]
1-[2-[(4-(4-hydroxy)benzoyl-1-piperidinyl)carbonyl]-2,3-dihydro-4H--
1,4-benzoxazin-4-yl]-ethanone,
[0038]
1-[2-(2,3-dihydro-1,4-benzodioxin-2-yl)ethyl]-4-(4-methylphenyl)-4--
piperidinol, or a pharmaceutically acceptable salt thereof.
[0039] In another aspect, the present invention includes compounds
of formula I:
##STR00002##
[0040] wherein
[0041] X is --O-- or --NR.sup.1--, where R.sup.1 is hydrogen,
alkyl, acyl, alkylsulfinyl, alkylsufonyl, amido or
--C(O)-aminoalkyl;
[0042] Y is --C(O)-- or --CH.sub.2C(O)--;
[0043] R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are each,
independently, hydrogen, halogen, hydroxy, cyano, nitro, amino,
alkylamino, dialkylamino, carboxyl, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocycle, heterocyclealkyl, aroyl, acyl,
alkoxy, aryloxy, cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy,
heteroarylalkyloxy, alkythio, arylthio, alkylsulfinyl,
alkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl or
heteroaryloxycarbonyl;
[0044] R.sup.6 and R.sup.7 are each hydrogen, or R.sup.6 and
R.sup.7, together with the carbon atom to which they are attached,
form a --C(O)-- group;
[0045] R.sup.8 is hydrogen or alkyl;
[0046] Z is arylalkyl; and
[0047] m is 1 or 2;
[0048] wherein, when present, any aryl, heteroaryl or heterocycle
group may optionally be substituted by halogen, hydroxy, cyano,
nitro, amino, alkylamino, dialkylamino, arylamino, diarylamino,
amido, carboxyl, alkyl, halogenated alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocycle, heterocyclealkyl, aroyl, acyl,
alkoxy, aryloxy, heteroaryloxy, cycloalkyloxy, cycloalkylalkyloxy,
arylalkyloxy, heteroarylalkyloxy, alkythio, arylthio,
alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl,
heteroarylsulfinyl, heteroarylsulfonyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, and combinations
thereof;
[0049] and pharmaceutically acceptable salts or solvates (e.g.,
hydrates) or N-oxides thereof, or solvates of pharmaceutically
acceptable salts thereof, or pharmaceutically acceptable salts or
solvates of N-oxides thereof; or prodrugs thereof;
[0050] with the provisos that:
[0051] when m is 1 and X is --O--, then Z is optionally substituted
4-fluorobenzyl,
[0052] and said compound is not:
[0053]
[4-[(2-chloro-4-fluorophenyl)methyl]-1-piperazinyl](2,3-dihydro-1,4-
-benzodioxin-2-yl)-methanone,
[0054]
1-[2,3-dihydro-2-[[4-(1-naphthalenylmethyl)-1-piperazinyl]carbonyl]-
-4H-1,4-benzoxazin-4-yl]-ethanone,
[0055]
1-[2,3-dihydro-2-[[4-[[4-(trifluoromethyl)phenyl]methyl]-1-piperazi-
nyl]carbonyl]4H-1,4-benzoxazin-4-yl]-ethanone,
[0056]
[4-(ethylsulfonyl)-3,4-dihydro-2H-1,4-benzoxazin-2-yl][4-(phenylmet-
hyl)-1-piperazinyl]-methanone,
[0057]
2-[2-oxo-2-[4-(phenylmethyl)-1-piperazinyl]ethyl]-2H-1,4,-benzoxazi-
n-3(4H)-one, or
[0058]
1-2[[hexahydro-4-[(4-methoxyphenyl)methyl]-1H-1,4-diazepin-1-yl]car-
bonyl]-2,3 -dihydro-4H-1,4-benzoxazin-4-yl]-ethanone,
[0059] or a pharmaceutically acceptable salt thereof.
[0060] In additional embodiments, one of R.sup.2-R.sup.5 is halogen
(e.g., Cl). For example, one of R.sup.2-R.sup.5 is halogen (e.g.,
Cl) and the others of R.sup.2-R.sup.5 are hydrogen. For further
example, R.sup.2, R.sup.4 and R.sup.5 are hydrogen and R.sup.3 is
halogen (e.g., Cl). In another embodiment, two of R.sup.2-R.sup.5
are halogen (e.g., Cl). For example, R.sup.2 and R.sup.5 are
hydrogen and R.sup.3 and R.sup.4 are halogen (e.g., Cl).
[0061] In certain embodiments, when X is --NR.sup.1--, then
R.sup.2, R.sup.4 and R.sup.5 are hydrogen and R.sup.3 is halogen
(e.g., Cl).
[0062] In one embodiment, when R.sup.6 and R.sup.7, together with
the carbon atom to which they are attached, form a --C(O)-- group,
then Y is --C(O)--.
[0063] In further embodiments, when X is --O--, then Y is
--C(O)--.
[0064] In additional embodiments, X is --NR.sup.1--, where R.sup.1
is hydrogen, alkyl (e.g., methyl), acyl (e.g., --C(O)CH.sub.3),
alkylsufonyl (e.g., --SO.sub.2CH.sub.3), amido (--C(O)NH.sub.2) or
--C(O)-aminoalkyl (e.g., --C(O)CH.sub.2NHMe,
--C(O)CH.sub.2NMe.sub.2).
[0065] In certain embodiments, R.sup.8 is alkyl (e.g., methyl). In
other embodiments, R.sup.8 is hydrogen.
[0066] In further embodiments, Z is 4-halo-substituted arylalkyl
(e.g., 4-halo-substituted benzyl, such as 4-fluorobenzyl). In
further embodiments, Z is 4-halo-substituted arylalkyl (e.g.,
4-halo-substituted benzyl, such as 4-fluorobenzyl) that is not
additionally substituted by halogen. In further embodiments, Z is
4-halo-substituted arylalkyl (e.g., 4-halo-substituted benzyl, such
as 4-fluorobenzyl) that is not additionally substituted by alkoxy
(e.g., methoxy). In further embodiments, Z is 4-halo-substituted
arylalkyl (e.g., 4-halo-substituted benzyl, such as 4-fluorobenzyl)
that is not additionally substituted by cyano. In further
embodiments, Z is 4-halo-substituted arylalkyl (e.g.,
4-halo-substituted benzyl, such as 4-fluorobenzyl) that is not
additionally substituted by halogen, alkoxy or cyano.
[0067] In additional embodiments, Z is 4-halo-substituted arylalkyl
(e.g., 4-halo-substituted benzyl, such as 4-fluorobenzyl) that is
not further substituted. In exemplary embodiments, Z is
unsubstituted 4-fluoro-arylalkyl, such as unsubstituted
4-fluorobenzyl.
[0068] In certain embodiments, the present invention includes
compounds of formula (I) wherein
[0069] X is O or --NR.sup.1, where R.sup.1 is hydrogen, alkyl,
acyl, alkylsufonyl, amido or --C(O)-aminoalkyl;
[0070] Y is --C(O)-- or --CH.sub.2C(O)--;
[0071] R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are each,
independently, hydrogen or halogen;
[0072] R.sup.6 and R.sup.7 are each hydrogen, or R.sup.6 and
R.sup.7, together with the carbon atom to which they are attached,
form a --C(O)-- group;
[0073] R.sup.8 is hydrogen or alkyl;
[0074] m is 1 or 2; and
[0075] Z is arylalkyl;
[0076] with the proviso that when m is 1 and X is O, then Z is
4-fluorobenzyl.
[0077] In certain embodiments, the compound of formula I is
selected from:
[0078]
(6-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[(R)-4-(4-fluoro-benzy-
l)-2-methyl-piperazin-1-yl]-methanone,
[0079]
(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-[(R)-4-(4-fluoro-benzyl)-2-meth-
yl-piperazin-1-yl]-methanone,
[0080]
(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-[4-(4-fluoro-benzyl)-piperazin--
1-yl]-methanone,
[0081]
(6-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[4-(4-fluoro-benzyl)-p-
iperazin-1-yl]-methanone,
[0082]
(6-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[4-(4-fluoro-benzyl)-[-
1,4]diazepan-1yl]-methanone,
[0083]
(6,7-Dichloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[(R)-4-(4-fluoro-b-
enzyl)-2-methyl-piperazin-1-yl]-methanone,
[0084]
(6,7-Dichloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[4-(4-fluoro-benzy-
l)-[1,4]diazepan-1-yl]-methanone,
[0085]
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[(R)-4-(4-fluoro-be-
nzyl)-2-methyl-piperazin-1-yl]-methanone,
[0086]
(6-Chloro-3,4-d,ihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-benzy-
l)-piperazin-1-yl]-methanone,
[0087]
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-benzyl-
)-[1,4]diazepan-1-yl]-methanone,
[0088]
6-Chloro-2-[4-(4-fluoro-benzyl)-[1,4]diazepane-1-carbonyl]-2,3-dihy-
dro-benzo[1,4]oxazine-4-carboxylic acid amide,
[0089]
(6-Chloro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[(R)-4-(4--
fluoro-benzyl)-2-methyl-piperazin-1-yl]-methanone,
[0090]
(6-Chloro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluo-
ro-benzyl)-[1,4]diazepan-1-yl]-methanone,
[0091]
6-Chloro-2-[(R)-4-(4-fluoro-benzyl)-2-methyl-piperazine-1-carbonyl]-
-4H-benzo[1,4]oxazin-3-one,
[0092]
1-{6-Chloro-2-[4-(4-fluoro-benzyl)-piperazine-1-carbonyl]-2,3-dihyd-
ro-benzo[1,4]oxazin-4-yl}-ethanone,
[0093]
(6-Chloro-4-methanesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[-
4-(4-fluoro-benzyl)-piperazin-1-yl]-methanone,
[0094]
1-{6-Chloro-2-[4-(4-fluoro-benzyl)-piperazine-1-carbonyl]-2,3-dihyd-
ro-benzo[1,4]oxazin-4-yl}-2-dimethylamino-ethanone,
[0095]
(6-Chloro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluo-
ro-benzyl)-piperazin-1-yl]-methanone,
[0096]
1-{6-Chloro-2-[4-(4-fluoro-benzyl)-piperazine-1-carbonyl]-2,3-dihyd-
ro-benzo[1,4]oxazin-4-yl}-2-methylamino-ethanone,
[0097]
2-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-1-[(R)-4-(4-fluor-
o-benzyl)-2-methyl-piperazin-1-yl]-ethanone,
[0098]
2-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-1-[4-(4-fluoro-be-
nzyl)-[1,4]diazepan-1-yl]-ethanone, and
[0099]
(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[(R)-4-(4-
-fluoro-benzyl)-2-methyl-piperazin-1-yl]-methanone,
[0100] wherein free base forms listed above can also be in the form
of a pharmaceutically acceptable salt,
[0101] wherein a compound listed above (in either a free base form
or in the form of a pharmaceutically acceptable salt) can also be
in the form of a solvate (such as a hydrate),
[0102] wherein a compound listed above (in either a free base form
or in the form of a pharmaceutically acceptable salt) can also be
in the form of an N-oxide,
[0103] wherein a compound listed above (in a free base form or
solvate or N-oxide thereof, or in the form of a pharmaceutically
acceptable salt or solvate thereof,) can also be in the form of a
polymorph, and
[0104] wherein if the compound exhibits chirality it can be in the
form of a mixture of enantiomers such as a racemate or a mixture of
diastereomers, or can be in the form of a single enantiomer or a
single diastereomer.
[0105] In additional embodiments, the compound of formula I is
selected from:
[0106]
(6-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[4-(4-fluoro-benzyl)-2-
-methyl-piperazin-1-yl]-methasone,
[0107]
(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-[4-(4-fluoro-benzyl)-2-methyl-p-
iperazin-1-yl]-methanone,
[0108]
(6,7-Dichloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[4-(4-fluoro-benzy-
l)-2-methyl-piperazin-1-yl]-methanone,
[0109]
(6-Chloro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluo-
ro-benzyl)-2-methyl-piperazin-1-yl]-methanone, and
[0110]
(6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)--
[(R)-4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-methanone,
[0111] wherein free base forms listed above can also be in the form
of a pharmaceutically acceptable salt,
[0112] wherein a compound listed above (in either a free base form
or in the form of a pharmaceutically acceptable salt) can also be
in the form of a solvate (such as a hydrate),
[0113] wherein a compound listed above (in either a free base form
or in the form of a pharmaceutically acceptable salt) can also be
in the form of an N-oxide,
[0114] wherein a compound listed above (in a free base form or
solvate or N-oxide thereof, or in the form of a pharmaceutically
acceptable salt or solvate thereof,) can also be in the form of a
polymorph, and
[0115] wherein if the compound exhibits chirality it can be in the
form of a mixture of enantiomers such as a racemate or a mixture of
diastereomers, or can be in the form of a single enantiomer or a
single diastereomer.
[0116] In another aspect, the present invention includes compounds
of formula II:
##STR00003##
[0117] wherein
[0118] X.sup.1 is O or --NR.sup.9, where R.sup.9 is hydrogen,
alkyl, acyl, alkylsulfinyl, alkylsulfonyl, amido or
--C(O)-aminoalkyl;
[0119] Y.sup.1 is --C(O)--, --CH.sub.2C(O)--, --CH.sub.2-- or
--CH.sub.2CH.sub.2--;
[0120] R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are each,
independently, hydrogen, halogen, hydroxy, cyano, nitro, amino,
alkylamino, dialkylamino, carboxyl, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocycle, heterocyclealkyl, aroyl, acyl,
alkoxy, aryloxy, cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy,
heteroarylalkyloxy, alkythio, arylthio, alkylsulfinyl,
alkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl or
heteroaryloxycarbonyl;
[0121] R.sup.14 and R.sup.15 are each hydrogen, or R.sup.14 and
R.sup.15, together with the carbon atom to which they are attached,
form a --C(O)-- group;
[0122] R.sup.16 is hydrogen or alkyl;
[0123] p is 1 or 2; and
[0124] Z.sup.1 are Z.sup.2 are each, independently, hydrogen, aryl,
heteroaryl, heterocycle, arylalkyl, heteroarylalkyl or
heterocyclealkyl; with the proviso that at least one of Z.sup.1 or
Z.sup.2 is other than hydrogen;
[0125] wherein, when present, any aryl, heteroaryl or heterocycle
may optionally be substituted by halogen, hydroxy, cyano, nitro,
amino, alkylamino, dialkylamino, arylamino, diarylamino, amido,
carboxyl, alkyl, halogenated alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycle, heterocyclealkyl, aroyl, acyl, alkoxy, aryloxy,
heteroaryloxy, cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy,
heteroarylalkyloxy, alkythio, arylthio, alkylsulfinyl,
alkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroarylsulfinyl,
heteroarylsulfonyl, alkoxycarbonyl, aryloxycarbonyl,
heteroaryloxycarbonyl, and combinations thereof;
[0126] and pharmaceutically acceptable salts or solvates (e.g.,
hydrates) or N-oxides thereof, or solvates of pharmaceutically
acceptable salts thereof, or pharmaceutically acceptable salts or
solvates of N-oxides thereof; or prodrugs thereof.
[0127] In additional embodiments, one of R.sup.10--R.sup.13 is
halogen (e.g., Cl). For example, one of R.sup.10--R.sup.13 is
halogen (e.g., Cl) and the others of R.sup.10--R.sup.13 are
hydrogen. For further example, R.sup.10, R.sup.12 and R.sup.13 are
hydrogen and R.sup.11 is halogen (e.g., Cl). In another embodiment,
two of R.sup.10--R.sup.13 are halogen (e.g., Cl).
[0128] In certain embodiments, X is --NR.sup.9, where R.sup.9 is
hydrogen, alkyl, acyl, alkylsulfinyl, alkylsulfonyl, amido or
--C(O)-aminoalkyl. For example X is --NH--.
[0129] In further embodiments, one of Z.sup.1 and Z.sup.2 is
hydrogen and the other of Z.sup.1 and Z.sup.2 is arylalkyl (e.g.,
benzyl), such as as 4-halo-substituted arylalkyl (e.g.,
4-fluorobenzyl). For example, Z.sup.1 is hydrogen and Z.sup.2 is
arylalkyl (e.g., benzyl), such as as 4-halo-substituted arylalkyl
(e.g., 4-fluorobenzyl). For further example, Z.sup.2 is hydrogen
and Z.sup.1 is arylalkyl (e.g., benzyl), such as as
4-halo-substituted arylalkyl (e.g., 4-fluorobenzyl). In certain
embodiments, Z.sup.1 is hydrogen and Z.sup.2 is 4-fluorobenzyl. In
additional embodiments, Z.sup.2 is hydrogen and Z.sup.1 is
4-fluorobenzyl.
[0130] In certain embodiments, the present invention includes
compounds of formula II
[0131] wherein
[0132] X.sup.1 is --NR.sup.9, where R.sup.9 is hydrogen;
[0133] Y.sup.1 is --C(O)--, --CH.sub.2C(O)--, or
--CH.sub.2CH.sub.2--;
[0134] R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are each,
independently, hydrogen or halogen;
[0135] R.sup.14 and R.sup.15 are each hydrogen;
[0136] R.sup.16 is hydrogen;
[0137] p is 2; and
[0138] Z.sup.1 are Z.sup.2 are each, independently, hydrogen or
arylalkyl; with the proviso that at least one of Z.sup.1 or Z.sup.2
is arylalkyl.
[0139] In certain embodiments, the compound of formula II is
selected from:
[0140]
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[7-(4-fluoro-benzyl-
)-[1,4]oxazepan-4-yl]-methanone,
[0141]
2-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-1-[7-(4-fluoro-be-
nzyl)-[1,4]oxazepan-4-yl]-ethanone,
[0142]
2-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-1-[2-(4-fluoro-be-
nzyl)-[1,4]oxazepan-4-yl]-ethanone, and
[0143]
6-Chloro-2-{2-[2-(4-fluoro-benzyl)-[1,4]oxazepan-4-yl]-ethyl}-3,4-d-
ihydro-2H-benzo[1,4]oxazine,
[0144] wherein free base forms listed above can also be in the form
of a pharmaceutically acceptable salt,
[0145] wherein a compound listed above (in either a free base form
or in the form of a pharmaceutically acceptable salt) can also be
in the form of a solvate (such as a hydrate),
[0146] wherein a compound listed above (in either a free base form
or in the form of a pharmaceutically acceptable salt) can also be
in the form of an N-oxide,
[0147] wherein a compound listed above (in a free base form or
solvate or N-oxide thereof, or in the form of a pharmaceutically
acceptable salt or solvate thereof,) can also be in the form of a
polymorph, and
[0148] wherein if the compound exhibits chirality it can be in the
form of a mixture of enantiomers such as a racemate or a mixture of
diastereomers, or can be in the form of a single enantiomer or a
single diastereomer.
[0149] In a further aspect, the present invention includes
compounds of formula III:
##STR00004##
[0150] wherein
[0151] X.sup.2 is O or --NR.sup.17, where R.sup.17 is hydrogen,
alkyl, acyl, alkylsulfinyl, alkylsulfonyl, amido, --C(O)-aminoalkyl
or -alkylene-C(O)NR.sup.eR.sup.f, where R.sup.e and R.sup.f are
each, independently, hydrogen or alkyl;
[0152] Y.sup.2 is --C(O)--, --CH.sub.2C(O)--, --CH.sub.2CH.sub.2--
or --CH.sub.2--;
[0153] R.sup.18, R.sup.19, R.sup.20 and R.sup.21 are each,
independently, hydrogen, halogen, hydroxy, cyano, nitro, amino,
alkylamino, dialkylamino, carboxyl, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocycle, heterocyclealkyl, aroyl, acyl,
alkoxy, aryloxy, cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy,
heteroarylalkyloxy, alkythio, arylthio, alkylsulfinyl,
alkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl,
heteroaryloxycarbonyl --O-alkylene-CO.sub.2H,
--O-alkylene-C(O)NR.sup.xR.sup.y or NR.sup.x(O)-alkyl, in which
R.sup.x and R.sup.y are each, independently, hydrogen or alkyl;
[0154] R.sup.22 and R.sup.23 are each hydrogen, or R.sup.22 and
R.sup.23, together with the carbon atom to which they are attached,
form a --C(O)-group;
[0155] R.sup.24 and R.sup.25 are each, independently, hydrogen or
alkyl; and
[0156] R.sup.26 is hydrogen, hydroxyl, cyano or -alkylene-NH.sub.2;
wherein
[0157] when R.sup.26 is hydrogen, then X.sup.2 is --NR.sup.17-- and
Z.sup.3 is --C(O)-aryl, -C(O)-heteoraryl, --C(O)-arylalkyl, or
--C(O)-heteroarylalkyl; and
[0158] when R.sup.26 is hydroxyl, cyano or -alkylene-NH.sub.2, then
Z.sup.3 is arylalkyl or heteroarylalkyl;
[0159] wherein, when present, any aryl, heteroaryl or heterocycle
group may optionally be substituted by halogen, hydroxy, cyano,
nitro, amino, alkylamino, dialkylamino, arylamino, diarylamino,
amido, carboxyl, alkyl, halogenated alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocycle, heterocyclealkyl, aroyl, acyl,
alkoxy, aryloxy, heteroaryloxy, cycloalkyloxy, cycloalkylalkyloxy,
arylalkyloxy, heteroarylalkyloxy, alkythio, arylthio,
alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl,
heteroarylsulfinyl, heteroarylsulfonyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, and combinations
thereof;
[0160] and pharmaceutically acceptable salts or solvates (e.g.,
hydrates) or N-oxides thereof, or solvates of pharmaceutically
acceptable salts thereof, or pharmaceutically acceptable salts or
solvates of N-oxides thereof; or prodrugs thereof,
[0161] with the proviso that said compound is not:
[0162]
1-[2-[(4-benzoyl-1-piperidinyl)carbonyl]-2,3-dihydro-4H-1,4-benzoxa-
zin-4-yl]-ethanone,
[0163]
1-[2-[(4-(4-hydroxy)benzoyl-1-piperidinyl)carbonyl]-2,3-dihydro-4H--
1,4-benzoxazin-4-yl]-ethanone,
[0164]
1-[2-(2,3-dihydro-1,4-benzodioxin-2-yl)ethyl]-4-(4-methylphenyl)-4--
piperidinol, or a pharmaceutically acceptable salt thereof.
[0165] In additional embodiments, R.sup.18--R.sup.21 are each
hydrogen. In further embodiments one of R.sup.18--R.sup.21 is
halogen (e.g., Cl). For example, one of R.sup.18--R.sup.21 is
halogen (e.g., Cl) and the others of R.sup.18--R.sup.21 are
hydrogen. In another embodiment, two of R.sup.18--R.sup.21 are
halogen (e.g., Cl). In further embodiments, one of
R.sup.18--R.sup.21 is halogen (e.g., Cl) and another of
R.sup.18--R.sup.21 is alkoxy, hydroxyl, dialkylamino,
--O-alkylene-CO.sub.2H, --O-alkylene-C(O)NR.sup.xR.sup.y or
NR.sup.xC(O)-alkyl, in which R.sup.x and R.sup.y are each
independently hydrogen or alkyl.
[0166] For example, R.sup.18, R.sup.20 and R.sup.21 are hydrogen
and R.sup.19 is halogen (e.g., Cl). For further example, R.sup.19
is halogen (e.g., Cl) and R.sup.20 is hydrogen, alkoxy (e.g.,
methoxy, ethoxy), dialkylamino (e.g., -dimethylamino), hydroxyl,
--O-alkylene-CO.sub.2H, --O-alkylene-C(O)NR.sup.xR.sup.y or
NR.sup.xC(O)-alkyl, in which R.sup.x and R.sup.y are each
independently hydrogen or alkyl. For example, R.sup.19 is halogen
(e.g., Cl), R.sup.20 is hydrogen, alkoxy, hydroxyl, dialkylamino,
--O-alkylene-CO.sub.2H, --O-alkylene-C(O)NR.sup.xR.sup.y or
NR.sup.xC(O)-alkyl, in which R.sup.x and R.sup.y are each
independently hydrogen or alkyl, and R.sup.18 and R.sup.20 are
hydrogen. For example R.sup.18 and R.sup.20 are hydrogen, R.sup.19
is halogen (e.g., Cl) and R.sup.20 is hydrogen, methoxy, ethoxy,
hydroxyl, --NMe.sub.2, --OCH.sub.2CO.sub.2H,
--OCH.sub.2C(O)NH.sub.2, --OCH.sub.2C(O)NMe.sub.2 or
--NHC(O)CH.sub.3.
[0167] In certain embodiments, X.sup.2 is --NR.sup.17, where
R.sup.17 is hydrogen, alkyl, acyl, alkylsulfinyl, alkylsulfonyl,
amido, --C(O)-aminoalkyl or -alkylene-C(O)NR.sup.eR.sup.f. For
example R.sup.17 is hydrogen, alkyl, acyl, alkylsulfonyl,
--C(O)-aminoalkyl or -alkylene-C(O)NR.sup.eR.sup.f. In certain
embodiments, R.sup.e and R.sup.f are both hydrogen. For further
example, X.sup.2 is --NH-- or --CH.sub.2C(O)NH.sub.2. For example,
X.sup.2 is --NH--.
[0168] In further embodiments, R.sup.22 and R.sup.23 are
hydrogen.
[0169] In additional embodiments, R.sup.26 is hydroxyl, cyano or
-alkylene-NH.sub.2.
[0170] In further embodiments, R.sup.24 and R.sup.25 are alkyl. For
example, R.sup.24 and R.sup.25 are methyl.
[0171] In certain embodiments, R.sup.24 and R.sup.25 are alkyl and
R.sup.26 is hydroxyl. For example, R.sup.24 and R.sup.25 are methyl
and R.sup.26 is hydroxyl.
[0172] In further embodiments, R.sup.24 and R.sup.25 are hydrogen
and R.sup.26 is cyano or -alkylene-NH.sub.2. For example, R.sup.24
and R.sup.25 are hydrogen and R.sup.26 is cyano.
[0173] In additional embodiments, Z.sup.3 is halo-substituted
arylalkyl. In exemplary embodiments, Z.sup.3 is benzyl. For further
example, Z.sup.3 is halo-substituted benzyl, such as
4-halo-substitued benzyl (e.g., 4-fluorobenzyl,
4-chlorobenzyl).
[0174] In further embodiments, Z.sup.3 is substituted arylalkyl. In
exemplary embodiments, the benzyl hydrogens are substituted with
for example, but not limited to, hydroxyl, fluoro or difluoro
groups.
[0175] In certain embodiments, the present invention includes
compounds of formula III wherein
[0176] X.sup.2 is --NR.sup.17, where R.sup.17 is hydrogen, alkyl,
acyl, alkylsulfonyl, --C(O)-aminoalky or or
-alkylene-C(O)NR.sup.eR.sup.f, where R.sup.e and R.sup.f are each,
independently, hydrogen or alkyl;
[0177] Y.sup.2 is --C(O)--, --CH.sub.2C(O)--, --CH.sub.2CH.sub.2--
or --CH.sub.2--;
[0178] R.sup.18, R.sup.19, R.sup.20 and R.sup.21 are each,
independently, hydrogen, halogen, hydroxy, alkoxy, dialkylamino,
--O-alkylene-CO.sub.2H or --O-alkylene-C(O)NR.sup.xR.sup.y, in
which R.sup.x and R.sup.y are each, independently, hydrogen or
alkyl;
[0179] R.sup.22 and R.sup.23 are hydrogen;
[0180] R.sup.24 and R.sup.25 are each, independently, hydrogen or
alkyl; and
[0181] R.sup.26 is hydrogen, hydroxyl, cyano or -alkylene-NH.sub.2;
wherein
[0182] when R.sup.26 is hydrogen, then Z.sup.3 is --C(O)-aryl;
and
[0183] when R.sup.26 is hydroxyl, cyano or -alkylene-NH.sub.2, then
Z.sup.3 is arylalkyl.
[0184] In certain embodiments, the present invention includes
compounds of formula III wherein
[0185] X.sup.2 is --NR.sup.17, where R.sup.17 is hydrogen, alkyl,
acyl, alkylsulfonyl, --C(O)-aminoalkyl, dialkylamino or
-alkylene-C(O)NR.sup.eR.sup.f where R.sup.e and R.sup.f are each,
independently, hydrogen or alkyl;
[0186] Y.sup.2 is --C(O)--,
[0187] R.sup.18, R.sup.19, R.sup.20 and R.sup.21 are each,
independently, hydrogen, halogen, or alkoxy;
[0188] R.sup.22 and R.sup.23 are hydrogen;
[0189] R.sup.24 and R.sup.25 are hydrogen;
[0190] R.sup.26 is cyano; and
[0191] Z.sup.3 is arylalkyl.
[0192] For example, X.sup.2 is --NH--, Y.sup.2 is --C(O)--,
R.sup.18 and R.sup.21 are each hydrogen, R.sup.19 and R.sup.20 are
each, independently, halogen (e.g., Cl) or alkoxy (e.g., methoxy),
R.sup.22 and R.sup.23 are hydrogen, R.sup.24 and R.sup.25 are
hydrogen, R.sup.26 is cyano and Z.sup.3 is arylalkyl.
[0193] In additional embodiments, the compound of formula III is
represented by subformulas IIIa-IIIb:
##STR00005##
[0194] For example, in subformula IIIa, X.sup.2 is NR.sup.17,
Y.sup.2 is --C(O)--, --CH.sub.2C(O)--, --CH.sub.2CH.sub.2-- or
--CH.sub.2--, R.sup.19 is halogen and R.sup.18, R.sup.20 and
R.sup.21 are hydrogen. In additional embodiments, R.sup.17 is
hydrogen.
[0195] For example, in subformula IIIb, X.sup.2 is NR.sup.17,
Y.sup.2 is --C(O)--, R.sup.19 is halogen and R.sup.18 and R.sup.21
are hydrogen, R.sup.20 is hydrogen, alkoxy (e.g., methoxy),
hydroxyl, O-alkylene-CO.sub.2H (e.g., --OCH.sub.2CO.sub.2H)-- or
--O-alkylene-C(O)NR.sup.xR (e.g., --OCH.sub.2C(O)NH.sub.2,
--OCH2C(O)NMe.sub.2).
[0196] In certain embodiments, the compound of formula III is
selected from:
[0197]
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-benzoy-
l)-piperidin-1-yl]-methanone,
[0198]
1-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fluor-
o-benzyl)-piperidine-4-carbonitrile,
[0199]
1-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)-4-(4-fluoro-
-benzyl)-piperidin-4-yl)-methylamine,
[0200]
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0201]
4-(4-Chloro-benzyl)-1-(6-chloro-3,4-dihydro-2H-1-benzo[1,4]oxazine--
2-carbonyl)-piperidine-4-carbonitrile,
[0202]
[4-(4-Chloro-benzyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-(6-chlo-
ro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-methanone,
[0203]
4-(4-Chloro-benzyl)-1-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-y-
lmethyl)-3,3-dimethyl-piperidin-4-ol,
[0204]
1-(6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-c-
arbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0205]
1-(6-Chloro-7-hydroxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0206]
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3-
,4-dihydro-2H-benzo[1,4]oxazin-7-yloxy}-acetic acid,
[0207]
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3-
,4-dihydro-2H-benzo[1,4]oxazin-7-yloxy}-acetamide,
[0208]
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3-
,4-dihydro-2H-benzo[1,4]oxazin-7-yloxy}-N,N-dimethyl-acetamide,
[0209]
1-(6-Chloro-7-ethoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0210]
1-[6-Chloro-4-(2-dimethylamino-acetyl)-7-methoxy-3,4-dihydro-2H-ben-
zo[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0211]
1-(4-Acetyl-6-chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-c-
arbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0212]
1-[4-(4-Chloro-benzyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-2-(6--
chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-ethanone,
[0213]
4-(4-Chloro-benzyl)-1-[2-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin--
2-yl)-ethyl]-3,3-dimethyl-piperidin-4-ol,
[0214]
1-[2-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-ethyl]-4-(4-fl-
uoro-benzyl)-3,3-dimethyl-piperidin-4-ol,
[0215]
1-(6-Chloro-4-methanesulfonyl-7-methoxy-3,4-dihydro-2H-benzo[1,4]ox-
azine-2-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0216]
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-
-methoxy-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetamide,
[0217]
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0218]
N-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3-
,4-dihydro-2H-benzo[1,4]oxazin-7-yl}-acetamide,
[0219]
4-(4-Fluoro-benzyl)-1-(7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-
-carbonyl)-piperidine-4-carbonitrile,
[0220]
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-l-carbonyl]-7-me-
thoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid amide,
[0221]
1-(7-Bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4--
(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0222]
1-(6-Chloro-8-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0223]
1-(6,7-Dichloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-f-
luoro-benzyl)-piperidine-4-carbonitrile,
[0224]
1-(6-Chloro-7-isopropoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbony-
l)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0225]
1-(4-Acetyl-6-chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazi-
ne-2-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0226]
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-
-dimethylamino-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetamide,
[0227]
1-(6-Chloro-7-dimethylamino-4-methanesulfonyl-3,4-dihydro-2H-benzo[-
1,4]oxazine-2-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0228]
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-
-isopropoxy-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetamide,
[0229]
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-
-ethoxy-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetamide,
[0230]
1-(6-Chloro-7-ethoxy-4-methanesulfonyl-3,4-dihydro-2H-benzo[1,4]oxa-
zine-2-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0231]
1-(6-Chloro-7-pyrrolidin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-ca-
rbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0232]
1-(7-Azetidin-1-yl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0233]
1-(6-Chloro-7-difluoromethoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-ca-
rbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0234]
1-(7-Chloro-6-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0235]
1-(6-Chloro-7-diethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbo-
nyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0236]
1-(6-Chloro-7-morpholin-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-car-
bonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0237]
(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-flu-
oro-phenoxy)-piperidin-1-yl]-methanone,
[0238]
1-[6-Chloro-4-(2-hydroxy-ethyl)-7-methoxy-3,4-dihydro-2H-benzo[1,4]-
oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0239]
1-[6-Chloro-7-dimethylamino-4-(2-hydroxy-ethyl)-3,4-dihydro-2H-benz-
o[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0240]
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-l-carbonyl]-7-di-
methylamino-2,3-dihydro-benzo[1,4]oxazine-4-carbonitrile,
[0241]
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-4-carbonitrile,
[0242]
1-(6-Chloro-7-methylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbon-
yl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0243]
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-
-methoxy-2,3-dihydro-benzo[1,4]oxazin-4-yl}-N-methyl-acetamide,
[0244]
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-4-carbonitrile,
[0245]
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-me-
thoxy-2,3-dihydro-benzo[1,4]oxazine-4-carbonitrile,
[0246]
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carboxylic acid ethyl ester,
[0247]
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carboxylic acid ethyl
ester,
[0248]
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-pyridin-4-ylmethyl-piperidine-4-carbonitrile,
[0249]
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-pyridin-4-ylmethyl-piperidine-4-carbonitrile,
[0250]
(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-flu-
oro-benzyl)-4-hydroxymethyl-piperidin-1-yl]-methanone,
[0251]
(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4--
(4-fluoro-benzyl)-4-hydroxymethyl-piperidin-1-yl]-methanone,
[0252]
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidine-4-carbonitrile,
[0253]
1-[6-Chloro-7-dimethylamino-4-(2-dimethylamino-ethyl)-3,4-dihydro-2-
H-benzo[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitr-
ile,
[0254]
1-[6-Chloro-4-(2-dimethylamino-ethyl)-7-methoxy-3,4-dihydro-2H-benz-
o[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0255]
(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-flu-
oro-benzyl)-4-imidazol-1-ylmethyl-piperidin-1-yl]-methanone,
[0256]
1-(6-Chloro-7-ethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4--
(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0257]
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidine-4-carbonitrile,
[0258]
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-3-(4-fluoro-benzyl)-pyrrolidine-3-carbonitrile,
[0259]
{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-
-dihydro-2H-benzo[1,4]oxazin-7-yl}-methyl-cyanamide,
[0260]
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-[difluoro-(4-fluoro-phenyl)-methyl]-piperidine-4-carbonitrile,
[0261]
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-[difluoro-(4-fluoro-phenyl)-methyl]-piperidine-4-carbonitrile,
[0262]
1-[6-Chloro-7-(1H-pyrazol-4-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2--
carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0263]
6-Chloro-7-[methyl-(2H-tetrazol-5-yl)-amino]-3,4-dihydro-2H-benzo[1-
,4]oxazine-2-carboxylic acid
[3-cyano-3-(4-fluoro-benzyl)-pentyl]-methyl-amide,
[0264]
1-[6-Chloro-7-(2H-tetrazol-5-ylamino)-3,4-dihydro-2H-benzo[1,4]oxaz-
ine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0265]
1-[6-Chloro-7-dimethylamino-4-(2,2,2-trifluoro-acetyl)-3,4-dihydro--
2H-benzo[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonit-
rile,
[0266]
1-[6-Chloro-7-methoxy-4-(2,2,2-trifluoro-acetyl)-3,4-dihydro-2H-ben-
zo[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0267]
1-(6-Chloro-7-methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0268]
1-(6-Chloro-7-imidazol-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0269]
1-[6-Chloro-7-methoxy-4-(2H-tetrazol-5-yl)-3,4-dihydro-2H-benzo[1,4-
]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0270]
4-(4-Fluoro-benzyl)-1-(quinoxaline-2-carbonyl)-piperidine-4-carboni-
trile,
[0271]
4-(4-Fluoro-benzyl)-1-([1,2,4]triazolo[1,5-a]pyrimidine-2-carbonyl)-
-piperidine-4-carbonitrile,
[0272]
4-(4-Fluoro-benzyl)-1-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-piperi-
dine-4-carbonitrile
[0273]
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,3--
dihydro-benzo[1,4]oxazine-4-carbonitrile,
[0274]
1-[6-Chloro-4-(2H-tetrazol-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-
-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0275]
1-[6-Chloro-4-(1H-[1,2,4]triazol-3-yl)-3,4-dihydro-2H-benzo[1,4]oxa-
zine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0276]
1-(6-Chloro-7-pyrrol-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbon-
yl)-4-(4-fluoro-benzyl)piperidine-4-carbonitrile,
[0277]
1-[6-Chloro-7-methoxy-4-(1H-[1,2,4]triazol-3-yl)-3,4-dihydro-2H-ben-
zo[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0278]
1-[6-Chloro-8-(1H-pyrazol-4-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2--
carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0279]
1-(6-Chloro-8-pyridin-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbo-
nyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0280]
1-(6-Chloro-8-thiophen-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0281]
1-(6-Chloro-7-thiophen-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0282]
1-(6-Chloro-7-pyridin-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbo-
nyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0283]
1-(6-Chloro-7-pyridin-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbo-
nyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0284]
1-[6-Chloro-7-(2-methyl-2H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[1,4]o-
xazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0285]
1-[6-Chloro-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-benzo[1,4]o-
xazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0286]
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0287]
1-(6-Chloro-7-pyrazol-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbo-
nyl)-4-(4fluoro-benzyl)-piperidine-4-carbonitrile,
[0288]
1-(6-Chloro-7-pyrimidin-5-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-car-
bonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0289] 1-(6-Chloro-7-hexa deuterio
dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fluoro-be-
nzyl)-piperidine-4-carbonitrile,
[0290]
1-(6-Chloro-7-furan-2-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbony-
l)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0291]
1-(6-Chloro-7-furan-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbony-
l)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0292]
1-[6-Chloro-7-(4-methyl-imidazol-1-yl)-3,4-dihydro-2H-benzo[1,4]oxa-
zine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0293]
1-[6-Chloro-7-(3-methyl-pyrazol-1-yl)-3,4-dihydro-2H-benzo[1,4]oxaz-
ine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0294]
1-(6-Chloro-7-[1,2,4]triazol-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine--
2-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0295]
1-(6-Chloro-7-[1,2,3]triazol-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine--
2-carbonyl]-4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0296]
1-(6-Chloro-4-methyl-7-oxazol-5-yl-3,4-dihydro-2H-benzo[1,4]oxazine-
-2-carbonyl)-4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0297]
1-[6-Chloro-7-dimethylamino-4-(1H-[1,2,4]triazol-3-yl)-3,4-dihydro--
2H-benzo[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonit-
rile,
[0298]
1-[6-Chloro-7-(6-fluoro-pyridin-3-yl)-3,4-dihydro-2H-benzo[1,4]oxaz-
ine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0299]
1-[6-Chloro-7-(6-methoxy-pyridin-3-yl)-3,4-dihydro-2H-benzo[1,4]oxa-
zine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0300]
1-[6-Chloro-7-(2-methoxy-pyridin-3-yl)-3,4-dihydro-2H-benzo[1,4]oxa-
zine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0301]
1-(6-Chloro-7-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0302]
1-(6-Chloro-2-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-piperidine-4-carbonitrile,
[0303]
1-(6-Chloro-7-dimethylamino-2-methyl-3,4-dihydro-2H-benzo[1,4]oxazi-
ne-2-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0304]
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-di-
methylamino-2,3-dihydro-benzo[1,4]oxazine-4-carbonitrile,
[0305]
1-[6-Chloro-7-(2-methoxy-phenyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-
-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0306]
1-(6-Chloro-7-pyridin-2-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbo-
nyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0307]
1-(7-Acetyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0308]
1-(6-Chloro-7-oxazol-5-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbon-
yl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0309]
1-(4-Chloro-2-methyl-3,6,7,8-tetrahydro-9-oxa-1,3,6-triaza-cyclopen-
ta[a]naphthalene-8-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile-
,
[0310]
1-(4-Chloro-3,6,7,8-tetrahydro-9-oxa-1,3,6triazacyclopenta[a]naphth-
alene-8-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0311]
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4--
dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid methylamide,
[0312]
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4--
dihydro-2H-benzo[1,4]oxazine-7-carbonitrile,
[0313]
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4--
dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid dimethylamide,
and
[0314]
1-[6-Chloro-7-(2-methyl-thiazol-4-yl)-3,4-dihydro-2H-benzo[1,4]oxaz-
ine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile,
[0315] wherein free base forms listed above can also be in the form
of a pharmaceutically acceptable salt,
[0316] wherein a compound listed above (in either a free base form
or in the form of a pharmaceutically acceptable salt) can also be
in the form of a solvate (such as a hydrate),
[0317] wherein a compound listed above (in either a free base form
or in the form of a pharmaceutically acceptable salt) can also be
in the form of an N-oxide,
[0318] wherein a compound listed above (in a free base form or
solvate or N-oxide thereof, or in the form of a pharmaceutically
acceptable salt or solvate thereof,) can also be in the form of a
polymorph, and
[0319] wherein if the compound exhibits chirality it can be in the
form of a mixture of enantiomers such as a racemate or a mixture of
diastereomers, or can be in the form of a single enantiomer or a
single diastereomer.
[0320] In another aspect, the present invention includes compounds
of formula IV:
##STR00006##
[0321] wherein
[0322] X.sup.3 is O or --NR.sup.27, where R.sup.27 is hydrogen,
alkyl, acyl, alkylsulfinyl, alkylsulfonyl, amido or
--C(O)-aminoalkyl;
[0323] Y.sup.2 is --C(O)--, --CH.sub.2C(O)--, --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2NR', --C(O)NR.sup.z,
--CH.sub.2C(O)NR.sup.z or --CH.sub.2CH.sub.2N.sup.z, where R.sup.z
is hydrogen or alkyl;
[0324] R.sup.28, R.sup.29, R.sup.30 and R.sup.31 are each,
independently, hydrogen, halogen, hydroxy, cyano, nitro, amino,
alkylamino, dialkylamino, carboxyl, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocycle, heterocyclealkyl, aroyl, acyl,
alkoxy, aryloxy, cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy,
heteroarylalkyloxy, alkythio, arylthio, alkylsulfinyl,
alkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl or
heteroaryloxycarbonyl;
[0325] R.sup.32 and R.sup.33 are each hydrogen, or R.sup.32 and
R.sup.33, together with the carbon atom to which they are attached,
form a --C(O)-- group;
[0326] R.sup.34 is alkyl;
[0327] q is 0, 1, 2, 3 or 4; and
[0328] Z.sup.4 is arylalkyl;
[0329] wherein, when present, any aryl, heteroaryl or heterocycle
group may optionally be substituted by halogen, hydroxy, cyano,
nitro, amino, alkylamino, dialkylamino, arylamino, diarylamino,
amido, carboxyl, alkyl, halogenated alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocycle, heterocyclealkyl, aroyl, acyl,
alkoxy, aryloxy, heteroaryloxy, cycloalkyloxy, cycloalkylalkyloxy,
arylalkyloxy, heteroarylalkyloxy, alkythio, arylthio,
alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl,
heteroarylsulfinyl, heteroarylsulfonyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, and combinations
thereof;
[0330] and pharmaceutically acceptable salts or solvates (e.g.,
hydrates) or N-oxides thereof, or solvates of pharmaceutically
acceptable salts thereof, or pharmaceutically acceptable salts or
solvates of N-oxides thereof; or prodrugs thereof,
[0331] with the proviso that said compound is not:
[0332]
2,3-dihydro-N-[1-(phenylmethyl)-4-piperidinyl]-1,4-benzodioxin-2-ca-
rboxamide,
[0333] or a pharmaceutically acceptable salt thereof.
[0334] In certain embodiments, X.sup.3 is --NR.sup.27, where
R.sup.27 is hydrogen, alkyl, acyl, alkylsulfinyl, alkylsulfonyl,
amido or --C(O)-aminoalkyl. For example, X.sup.3 is --NH--.
[0335] In additional embodiments, Y.sup.2 is --C(O)NR.sup.z,
--CH.sub.2C(O)NR.sup.z or --CH.sub.2CH.sub.2NR.sup.z, where R.sup.z
is hydrogen or alkyl. For example Y.sup.2 is --C(O)NR.sup.z,
--CH.sub.2C(O)NR.sup.z or --CH.sub.2CH.sub.2NR.sup.z, where R.sup.z
is hydrogen.
[0336] In further embodiments, q is 0, 1 or 2. For example, q is 0
or 1. For further example, q is 0.
[0337] In additional embodiments, one of R.sup.28--R.sup.31 is
halogen (e.g., Cl). For example, one of R.sup.28--R.sup.31 is
halogen (e.g., Cl) and the others of R.sup.28--R.sup.31 are
hydrogen. For further example, R.sup.28, R.sup.30 and R.sup.31 are
hydrogen and R.sup.29 is halogen (e.g., Cl). In another embodiment,
two of R.sup.28--R.sup.31 are halogen (e.g., Cl).
[0338] In additional embodiments, Z.sup.4 is halo-substituted
arylalkyl. In exemplary embodiments, Z.sup.4 is benzyl. For further
example, Z.sup.4 is halo-substituted benzyl, such as
4-halo-substitued benzyl (e.g., 4-fluorobenzyl,
4-chlorobenzyl).
[0339] In certain embodiments, the present invention includes
compounds of formula IV
[0340] wherein [0341] X.sup.3 is --NR.sup.27, where R.sup.27 is
hydrogen; [0342] Y.sup.2 is --C(O)NR.sup.z, --CH.sub.2C(O)NR.sup.z
or --CH.sub.2CH.sub.2NR.sup.z, where R.sup.z is hydrogen; [0343]
R.sup.28, R.sup.29, R.sup.30 and R.sup.31 are each, independently,
hydrogen or halogen; [0344] R.sup.32 and R.sup.33 are each
hydrogen; [0345] q is 0; and [0346] Z.sup.4 is arylalkyl.
[0347] In certain embodiments, the compound of formula IV is
selected from:
[0348] 6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
[1-(4-fluoro-benzyl)-piperidin-4-yl]-amide,
[0349]
N-[1-(4-Chloro-benzyl)-piperidin-4-yl]-2-(6-chloro-3,4-dihydro-2H-b-
enzo[1,4]oxazin-2-yl)-acetamide,
[0350]
[1-(4-Chloro-benzyl)-piperidin-4-yl]-[2-(6-chloro-3,4-dihydro-2H-be-
nzo[1,4]oxazin-2-yl)-ethyl]-amine,
[0351]
6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid [1-(4-fluoro-benzyl)-piperidin-4-yl]-amide,
[0352]
6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid [1-(4-fluoro-benzyl)-4-hydroxy-piperidin-4-ylmethyl]-amide,
and
[0353]
6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxy-
lic acid
[1-(4-fluoro-benzyl)-4-hydroxy-piperidin-4-ylmethyl]-amide,
[0354] wherein free base forms listed above can also be in the form
of a pharmaceutically acceptable salt,
[0355] wherein a compound listed above (in either a free base form
or in the form of a pharmaceutically acceptable salt) can also be
in the form of a solvate (such as a hydrate),
[0356] wherein a compound listed above (in either a free base form
or in the form of a pharmaceutically acceptable salt) can also be
in the form of an N-oxide,
[0357] wherein a compound listed above (in a free base form or
solvate or N-oxide thereof, or in the form of a pharmaceutically
acceptable salt or solvate thereof,) can also be in the form of a
polymorph, and
[0358] wherein if the compound exhibits chirality it can be in the
form of a mixture of enantiomers such as a racemate or a mixture of
diastereomers, or can be in the form of a single enantiomer or a
single diastereomer.
[0359] As used herein the term "halogen" means F, Cl, Br, and
I.
[0360] The term "alkyl" means a substituted or unsubstituted
saturated hydrocarbon radical which may be straight-chain or
branched-chain and may comprise about 1 to about 20 carbon atoms,
for instance 1 to 12 carbon atoms, such as 1 to 8 carbon atoms,
e.g., 1 to 4 carbon atoms. Suitable alkyl groups include, but are
not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,
tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,
and dodecyl. Other examples of suitable alkyl groups include, but
are not limited to, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or
2,2-dimethylpropyl, 1-ethylpropyl, 1-, 2-, 3- or 4-methylpentyl,
1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or
2-ethylbutyl, ethylmethylpropyl, trimethylpropyl, methylhexyl,
dimethylpentyl, ethylpentyl, ethylmethylbutyl, dimethylbutyl, and
the like.
[0361] Substituted alkyl groups are alkyl groups as described above
which are substituted in one or more positions by, e.g., deuterium,
halogen, hydroxyl, amino, carboxy, alkylamino, dialkylamino, aryl,
heteroaryl, alkoxy, nitro and cyano, and combinations thereof.
[0362] The term "halogenated alkyl" means a saturated hydrocarbon
radical which may be straight-chain or branched-chain and may
comprise about 1 to about 20 carbon atoms, for instance 1 to 12
carbon atoms, such as 1 to 8 carbon atoms, e.g., 1 to 4 carbon
atoms, that is substituted by one ore more halogens, such as, but
not limited to, --CF.sub.3, CF.sub.2CF.sub.3, CHF.sub.2, CH.sub.2F,
and the like. The use of the term "halogenated alkyl" should not be
construed to mean that a "substituted alkyl" group may not be
substituted by one or more halogens.
[0363] The term "alkenyl" means a substituted or unsubstituted
hydrocarbon radical which may be straight-chain or branched-chain,
which contains one or more carbon-carbon double bonds, and which
may comprise about 1 to about 20 carbon atoms, such as 1 to 12
carbon atoms, for instance 1 to 6 carbon atoms. Suitable alkenyl
groups include ethenyl, propenyl, butenyl, etc.
[0364] Substituted alkenyl groups are alkenyl groups as described
above which are substituted in one or more positions by, e.g.,
halogen, hydroxyl, amino, carboxy, alkylamino, dialkylamino, aryl,
heteroaryl, alkoxy, nitro and cyano, and combinations thereof.
[0365] The term "alkylene" means a linear saturated divalent
hydrocarbon radical of one to six carbon atoms or a branched
saturated divalent hydrocarbon radical of three to six carbon atoms
unless otherwise stated e.g., methylene, ethylene, propylene,
1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the
like.
[0366] The term "alkynyl" means a substituted or unsubstituted
aliphatic hydrocarbon radical which may be straight-chain or
branched-chain and which contains one or more carbon-carbon triple
bonds. Preferably the alkynyl group contains 2 to 15 carbon atoms,
such as 2 to 12 carbon atoms, e.g., 2 to 8 carbon atoms. Suitable
alkynyl groups include ethynyl, propynyl, butynyl, etc.
[0367] Substituted alkynyl groups are alkynyl groups as described
above which are substituted in one or more positions by, e.g.,
halogen, hydroxyl, amino, carboxy, alkylamino, dialkylamino, aryl,
heteroaryl, alkoxy, nitro and cyano, and combinations thereof.
[0368] The term "amino" means substituted or unsubstituted
--NH.sub.2. Substituted amino means a hydrogen substituted in one
or more positions by, for example, but not limited to cyano,
heterocycle, or heteroaryl group.
[0369] The term "alkylamino" means --NH(alkyl), wherein alkyl is
optionally substituted as described above. Substituted alkyl
includes, for example, but not limited to deuterium.
[0370] The term "dialkylamino" means --N(alkyl).sub.2, wherein
alkyl is substituted as described above.
[0371] The term "aryl" means a substituted or unsubstituted
aromatic monocyclic or bicyclic ring system comprising about 5 to
about 14 carbon atoms, e.g., about 6 to about 10 carbon atoms.
Suitable aryl groups include, but are not limited to, phenyl,
naphthyl, anthracenyl.
[0372] Substituted aryl groups include the above-described aryl
groups which are substituted one or more times by, for example, but
not limited to, halogen, hydroxyl, amino, carboxy, alkylamino,
dialkylamino, aryl, heteroaryl, alkoxy, nitro and cyano, and
combinations thereof.
[0373] The term "arylamino" means --NH(aryl), wherein aryl is as
described above.
[0374] The term "diarylamino" means --N(aryl).sub.2, wherein aryl
is as described above.
[0375] The term "amido" means --CONH.sub.2.
[0376] The term "aminoalkyl" means a -(alkylene)-amino,
-(alkylene)-alkylamino or -(alkylene)-dialkylamino group, wherein
the various groups are as described above.
[0377] The term "arylalkyl" refers to an -(alkylene)-aryl group in
which the aryl and alkylene portions are in accordance with the
previous descriptions. Suitable examples include, but are not
limited to, benzyl, 1-phenethyl, 2-phenethyl, phenpropyl,
phenbutyl, phenpentyl, and napthylmethyl.
[0378] The term "substituted arylalkyl" refers to -(alkylene)-aryl
group in which the alkylene hydrogens are substituted with, for
example, but not limited to, hydroxyl, fluoro or difluoro
groups.
[0379] The term "carboxyl" means --C(O)OH.
[0380] The term "cycloalkyl" means a monocyclic, bicyclic or
tricyclic nonaromatic saturated hydrocarbon radical having 3 to 10
carbon atoms, such as 3 to 8 carbon atoms, for example, 3 to 6
carbon atoms. Suitable cycloalkyl groups include, but are not
limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, norbornyl, 1-decalin, adamant-1-yl, and
adamant-2-yl. Other suitable cycloalkyl groups include, but are not
limited to, spiropentyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl,
spiro[2.4]heptyl, spiro[2.5]octyl, bicyclo[5.1.0]octyl,
spiro[2.6]nonyl, bicyclo[2.2.0]hexyl, spiro[3.3]heptyl,
bicyclo[4.2.0]octyl, and spiro[3.5]nonyl. Preferred cycloalkyl
groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The cycloalkyl group can be substituted, for example, by one or
more halogens and/or alkyl groups.
[0381] The term "cycloalkylalkyl" means a -(alkylene)-cycloalkyl in
which the cycloalkyl group is as previously described; e.g.,
cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or
cyclohexylmethyl, and the like.
[0382] The term "heteroaryl" means a substituted or unsubstituted
aromatic monocyclic or multicyclic ring system comprising 5 to 14
ring atoms, preferably about 5 to about 10 ring atoms and most
preferably 5 or 6 ring atoms, wherein at least one of the ring
atoms is an N, O or S atom. Suitable heteroaryl groups include, but
are not limited to furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,
pyridyl, pyrimidinyl, benzimidazolyl, indazolyl, indolyl,
quinolinyl, isoquinolinyl, naphthyridinyl and the like.
[0383] Substituted heteroaryl groups include the above-described
heteroaryl groups which are substituted one or more times by, for
example, but not limited to, halogen, hydroxyl, amino, carboxy,
alkyl, alkylamino, dialkylamino, aryl, heteroaryl, alkoxy, nitro
and and combinations thereof.
[0384] The term "heteroarylalkyl" refers to a
-(alkylene)-heteroaryl group wherein the heteroaryl and alkylene
portions are in accordance with the previous discussions. Suitable
examples include, but are not limited to, pyridylmethyl,
thiazolylmethyl, thienylmethyl, pyrimidinylmethyl, pyrazinylmethyl,
and isoquinolinylmethyl, and the like.
[0385] The term "heterocycle" means a substituted or unsubstituted
non-aromatic mono- or multicyclic ring system comprising 3 to 10
atoms, preferably 5 or 6, wherein at least one of the ring atoms is
an N, O or S atom. Suitable heterocyle groups include, but are not
limited to tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,
dihydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl,
thiomorpholinyl, morpholinyl, isoxazolinyl, and the like.
[0386] Substituted heterocycle groups include the above-described
heterocycle groups which are substituted one or more times by, for
example, halogen, amino, alkyl, hydroxy, carboxy, and combinations
thereof. Heterocycle groups may also be substituted by, e.g., aryl
or heteroaryl.
[0387] The term "heterocyclealkyl" refers to a
-(alkylene)-heterocycle group wherein the heterocycle and alkylene
portions are in accordance with the previous discussions.
[0388] The term "aroyl" means an aryl-C(O)--, in which the aryl
group is as previously described. Suitable aroyl groups include,
but are not limited to, benzoyl and 1-naphthoyl.
[0389] The term "acyl" means an HC(O)--, alkyl-C(O)--,
cycloalkyl-C(O)--, aryl-C(O)--, or heteroalkyl-C(O)--, in which the
various groups are as previously described, e.g., acetyl,
propionyl, benzoyl, pyridinylcarbonyl, and the like.
[0390] The term "alkoxy" means alkyl-O-- groups in which the alkyl
portion can be optionally substituted in accordance with the
previous discussion. Suitable alkoxy groups include, but are not
limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,
t-butoxy, pentoxy, hexoxy, heptoxy, octoxy, and the like. For
example, the alkoxy can be methoxy or ethoxy. For example, suitable
substituted alkoxy can be isopropoxy or difluoromethoxy.
[0391] The term "aryloxy" means an aryl-O-- group, in which the
aryl group is as previously described.
[0392] The term "heteroaryloxy" means an heteroaryl-O-- group, in
which the heteroaryl group is as previously described.
[0393] The term "cycloalkylalkyloxy" means a
--O-(alkylene)-cycloalkyl group, in which the cycloalkyl and
alkylene groups are as previously described.
[0394] The term "alkylthio" means an alkyl-S-- group, in which the
alkyl group is as previously described.
[0395] The term "arylthio" means an aryl-S-- group, in which the
aryl group is as previously described.
[0396] The term "alkylsulfinyl" means a --SOR radical where R is
alkyl as defined above, e.g., methylsulfinyl, ethylsulfinyl, and
the like.
[0397] The term "alkylsulfonyl" means a --SO.sub.2R radical where R
is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and
the like.
[0398] The term "arylsulfinyl" means a --SOR radical where R is
aryl as defined above, e.g., phenylsulfinyl, and the like.
[0399] The term "arylsulfonyl" means a --SO.sub.2R radical where R
is aryl as defined above, e.g., phenylsulfonyl, and the like.
[0400] The term "heteroarylsulfinyl" means a --SOR radical where R
is heteroaryl as defined above.
[0401] The term "heteroarylsulfonyl" means a --SO.sub.2R radical
where R is heteroaryl as defined above.
[0402] The term "alkoxycarbonyl" means an alkyl-O--C(O)-- group, in
which the alkyl group is as previously described.
[0403] The term "aryloxycarbonyl" means an aryl-O--C(O)-- group, in
which the aryl group is as previously described.
[0404] The term "heteroaryloxycarbonyl" means an
heteroaryl-O--C(O)-- group, in which the heteroaryl group is as
previously described.
[0405] The term "cycloalkyloxy" means a --O-cycloalkyl group in
which the cycloalkyl group is as previously described, e.g.,
cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and
the like.
[0406] The term "arylalkyloxy" means --O-(alkylene)-aryl group, in
which the aryl and alkylene groups are as previously described.
[0407] The term "heteroarylalkyloxy" means
--O-(alkylene)-heteroaryl group, in which the heteroaryl and
alkylene groups are as previously described.
[0408] One of ordinary skill in the art will recognize that
compounds of formulas I-IV can exist in different tautomeric and
geometrical isomeric forms. All of these compounds, including cis
isomers, trans isomers, diastereomic mixtures, racemates,
nonracemic mixtures of enantiomers, substantially pure, and pure
enantiomers, are within the scope of the present invention.
Substantially pure enantiomers contain no more than 5% w/w of the
corresponding opposite enantiomer, such as no more than 2%, for
example, no more than 1%.
[0409] The optical isomers can be obtained by resolution of the
racemic mixtures according to conventional processes, for example,
by the formation of diastereoisomeric salts using an optically
active acid or base or formation of covalent diastereomers.
Examples of appropriate acids are tartaric, diacetyltartaric,
dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid.
Mixtures of diastereoisomers can be separated into their individual
diastereomers on the basis of their physical and/or chemical
differences by methods known to those skilled in the art, for
example, by chromatography or fractional crystallization. The
optically active bases or acids are then liberated from the
separated diastereomeric salts. A different process for separation
of optical isomers involves the use of chiral chromatography (e.g.,
chiral HPLC columns), with or without conventional derivation,
optimally chosen to maximize the separation of the enantiomers.
Suitable chiral HPLC columns are manufactured by Diacel, e.g.,
Chiracel OD and Chiracel OJ among many others, all routinely
selectable. Enzymatic separations, with or without derivitization,
are also useful. Optically active compounds of formulas I-IV can
likewise be obtained by utilizing optically active starting
materials in chiral synthesis processes under reaction conditions
which do not cause racemization.
[0410] In addition, one of ordinary skill in the art will recognize
that the compounds can be used in different enriched isotopic
forms, e.g., enriched in the content of .sup.2H, .sup.3H, .sup.11C,
.sup.13C and/or .sup.14C. In one particular embodiment, the
compounds are deuterated. Such deuterated forms can be made the
procedure described in U.S. Pat. Nos. 5,846,514 and 6,334,997. As
described in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration
can improve the efficacy and increase the duration of action of
drugs.
[0411] Deuterium substituted compounds can be synthesized using
various methods such as described in: Dean, Dennis C.; Editor.
Recent Advances in the Synthesis and Applications of Radiolabeled
Compounds for Drug Discovery and Development. [In: Curr., Pharm.
Des., 2000; 6(10)] (2000), 110 pp. CAN 133:68895 AN 2000:473538
CAPLUS; Kabalka, George W.; Varma, Rajender S. The synthesis of
radiolabeled compounds via organometallic intermediates.
Tetrahedron (1989), 45(21), 6601-21, CODEN: TETRAB ISSN:0040-4020.
CAN 112:20527 AN 1990:20527 CAPLUS; and Evans, E. Anthony.
Synthesis of radiolabeled compounds, J. Radioanal. Chem. (1981),
64(1-2), 9-32. CODEN: JRACBN ISSN:0022-4081, CAN 95:76229 AN
1981:476229 CAPLUS.
[0412] Where applicable, the present invention also relates to
useful forms of the compounds as disclosed herein, such as base
free forms, and pharmaceutically acceptable salts or prodrugs of
all the compounds of the present invention for which salts or
prodrugs can be prepared. Pharmaceutically acceptable salts include
those obtained by reacting the main compound, functioning as a base
with an inorganic or organic acid to form a salt, for example,
salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane
sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid,
succinic acid, citric acid, formic acid, hydrobromic acid, benzoic
acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid,
and carbonic acid. Pharmaceutically acceptable salts also include
those in which the main compound functions as an acid and is
reacted with an appropriate base to form, e.g., sodium, potassium,
calcium, magnesium, ammonium, and choline salts. Those skilled in
the art will further recognize that acid addition salts of the
claimed compounds may be prepared by reaction of the compounds with
the appropriate inorganic or organic acid via any of a number of
known methods. Alternatively, alkali and alkaline earth metal salts
can be prepared by reacting the compounds of the invention with the
appropriate base via a variety of known methods.
[0413] The following are further examples of acid salts that can be
obtained by reaction with inorganic or organic acids: acetates,
aDIPEAtes, alginates, citrates, aspartates, benzoates,
benzenesulfonates, bisulfates, butyrates, camphorates,
digluconates, cyclopentanepropionates, dodecylsulfates,
ethanesulfonates, glucoheptanoates, glycerophosphates,
hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides,
hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates,
methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates,
palmoates, pectinates, persulfates, 3-phenylpropionates, picrates,
pivalates, propionates, succinates, tartrates, thiocyanates,
tosylates, mesylates and undecanoates.
[0414] For example, the pharmaceutically acceptable salt can be a
hydrochloride, a hydrobromide, a hydroformate, or a maleate. For
further example, the pharmaceutically acceptable salt is a
hydrochloride.
[0415] Preferably, the salts formed are pharmaceutically acceptable
for administration to mammals. However, pharmaceutically
unacceptable salts of the compounds are suitable as intermediates,
for example, for isolating the compound as a salt and then
converting the salt back to the free base compound by treatment
with an alkaline reagent. The free base can then, if desired, be
converted to a pharmaceutically acceptable acid addition salt.
[0416] One of ordinary skill in the art will also recognize that
some of the compounds of formulas I-IV can exist in different
polymorphic forms. As known in the art, polymorphism is an ability
of a compound to crystallize as more than one distinct crystalline
or "polymorphic" species. A polymorph is a solid crystalline phase
of a compound with at least two different arrangements or
polymorphic forms of that compound molecule in the solid state.
Polymorphic forms of any given compound are defined by the same
chemical formula or composition and are as distinct in chemical
structure as crystalline structures of two different chemical
compounds.
[0417] One of ordinary skill in the art will further recognize that
compounds of formulas I-IV can exist in different solvate forms.
Solvates of the compounds of the invention may also form when
solvent molecules are incorporated into the crystalline lattice
structure of the compound molecule during the crystallization
process.
[0418] The present invention also includes prodrugs of compounds of
formulas I-IV. The term prodrug is intended to represent covalently
bonded carriers, which are capable of releasing the active
ingredient of formulas I-IV when the prodrug is administered to a
mammalian subject. Release of the active ingredient occurs in vivo.
Prodrugs can be prepared by techniques known to one skilled in the
art. These techniques generally modify appropriate functional
groups in a given compound. These modified functional groups
however regenerate original functional groups by routine
manipulation or in vivo. Prodrugs of compounds of formulas I-IV
include compounds wherein a hydroxy, amino, carboxylic, or a
similar group is modified. Examples of prodrugs include, but are
not limited to esters (e.g., acetate, formate, and benzoate
derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of
hydroxy or amino functional groups in compounds of formulas I-IV),
amides (e.g., trifluoroacetylamino, acetylamino, and the like), and
the like. Prodrugs of compounds of formulas I-IV are also within
the scope of this invention.
[0419] The present invention also provides processes for preparing
the compounds of formulas I-IV. Suitable general reaction schemes
are shown below.
[0420] Compounds of formula I may be prepared by amide coupling
between appropriately substituted carboxylic acids and amines as
depicted in general synthetic schemes 1-5.
##STR00007##
[0421] Precursor A in Scheme 1 (where Ar is an aromatic ring, e.g.,
phenyl) is treated with a dihaloalkyl ester in the presence of a
base such as potassium tert-butoxide to obtain compound B as a
mixture of region- and stereo-isomeric products. Saponification of
compound B followed by amide coupling with an appropriately
substituted piperazine or homopiperizine unit D using suitable
coupling agents (e.g., EDC/HOBt) affords the desired compound
E.
##STR00008##
[0422] Protection of the free hydroxyl group of precursor A in
Scheme 2 with a suitable protecting agent (PG, such as benzyl
chloride) affords compound B. Conversion of compound B to C is
accomplished via a Dakin reaction using hydrogen peroxide and
sulfuric acid. Compound C is then reacted with epi-chlorohydrin in
the presence of a base such as cesium carbonate to obtain compound
D. Reductive deprotection of Compound D with hydrogen/Pd/C affords
Compound E. On treatment with strong alkali such as sodium
hydroxide, Compound E affords Compound F as a pure regio-siomer,
which is oxidized with e.g., CrO.sub.3/H.sub.2SO.sub.4, to afford
Compound G as a pure regio-isomer. Amide coupling between Compound
G and an appropriately substituted piperazine or homopiperazine
derivative (H) using suitable coupling agents (e.g., EDC/HOBt)
affords the desired Compound I.
##STR00009##
[0423] Compound B in Scheme 3 is prepared by reacting precursor A
with an .alpha.-haloalkyl diester in the presence of a suitable
base such as potassium tert-butoxide. Subjecting Compound B to
reductive conditions with iron affords Compound C, which upon
saponofication yields Compound D. Amide coupling between Compound D
and an appropriately substituted piperazine or homopiperazine
derivative (E) using suitable coupling agents (e.g., EDC/HOBt)
affords the desired Compound F.
##STR00010##
[0424] Compound B in Scheme 4 is prepared by reacting precursor A
with an appropriate dihaloalkyl ester in the presence of a suitable
base such as potassium tert-butoxide. Protection of the basic
nitrogen in Compound B using a protecting group (PG, such as BOC)
followed by saponification affords Compound C. Alternatively
Compound B in Scheme 4 may be prepared by reducing Compound C of
scheme 3 with e.g., borane.
[0425] Amide coupling between Compound C and an appropriately
substituted piperazine or homopiperazine derivative (D) using
suitable coupling agents (e.g., EDC/HOBt) followed by subsequent
removal of protecting group (PG) affords the desired Compound
F.
##STR00011##
[0426] Compound C in scheme 5 is prepared by reacting Compound A
with Compound B in presence of a suitable base such as potassium
tert-butoxide. Further treatment of compound C with base affords
Compound D. Protection of the free nitrogen of Compound D, for
example, as a tert-butyl carbamate derivative (Compound E),
followed by saponification affords Compound F. Amide coupling
between Compound F and an appropriately substituted piperazine or
homopiperazine derivative (G) using suitable coupling agents (e.g.,
EDC/HOBt) followed by subsequent removal of protecting group (PG)
affords the desired Compound I. Reduction of Compound I using
borane affords Compound J.
[0427] Compounds of formula II may be prepared by amide coupling
between appropriately substituted carboxylic acids and amines as
depicted in general synthetic schemes 6 and 7.
##STR00012##
[0428] Precursor A in scheme 6 may be prepared following the
synthetic method described in J. Am. Chem. Soc., 125, 10502-10503,
2003, using appropriate starting materials (PG=protecting group).
Reaction of precursor A with a haloalkyl acid chloride affords
Compound B, which is cyclised in presence of an anhydrous base such
as sodium hydride to afford Compound C. Reduction of Compound C
with borane followed by deprotection affords Compound E. Amide
coupling using an appropriate combination of Compounds E and F
using suitable coupling agents (e.g., EDC/HOBt) affords Compound G.
Reduction of Compound G using borohydride reducxing agents affords
Compound H. Carboxylic acids F may be prepared following the
synthetic route described for Compound I in scheme 5.
##STR00013##
[0429] Precursor B in scheme 7 is prepared by reacting Compound A
with an appropriate haloalkyl acid chloride in presence of a base
such as triethylamine. Cyclization of Compound B with sodium
hydride followed by C-alkylation of corresponding lithium enolate
affords Compound D, which on reduction with a metal hydride affords
Compound E. N-Deprotection of
[0430] Compound E followed by amide coupling with appropriate
Compound F using suitable coupling agents (e.g., EDC/HOBt) affords
Compound H. Reduction of Compound H with, e.g., borane affords
Compound I. Appropriate carboxylic acids (Compound F) may be
prepared following the synthetic route described for Compound I in
scheme 5.
[0431] Compounds of formula III may be prepared by amide coupling
between appropriate carboxylic acids and amines as depicted in
general synthetic scheme 8.
##STR00014## ##STR00015##
[0432] Compound B in Scheme 8 is prepared by alkylation of the
enolate of Compound A. Reaction of Compound B with ab appropriate
Grignard reagent affords Compound C, which after removal of
protecting group (PG) affords Compound D. Base assisted alkylation
of Compound E affords Compound G, which undergoes N-deprotection
with anhydrous acid to afford Compound H. Appropriate precursor
Compounds F are prepared following the synthetic route described
for Compound I in scheme 5.Amide coupling of Compound F with either
Compound D or Compound G, using suitable coupling reagents (e.g.,
EDC/HOBt) affords Compound I. Compound J is prepared by reduction
of the amide bond of Compound I with e.g., borane. Alkylation,
acylation or sulfonylation of the Compound I or Compound J
(X.dbd.N) affords Compound K.
[0433] Compounds of formula IV may be prepared by amide coupling
between appropriate carboxylic acids and amines as depicted in
general synthetic scheme 9.
##STR00016##
[0434] Appropriate precursors A in Scheme 9 are prepared following
the synthetic route described for Compound I in scheme 5. Amide
coupling, using suitable coupling reagents (e.g., EDC/HOBt) with an
appropriate aminopiperidine unit (Compound B) affords Compound C.
Reduction of the amide bond of Compound C using e.g., borane
affords Compound D.
[0435] The compounds of the invention can be administered alone or
as an active ingredient of a formulation. Thus, the present
invention also includes pharmaceutical compositions of compounds of
formulas I, II, III or IV, containing, for example, one or more
pharmaceutically acceptable carriers.
[0436] Numerous standard references are available that describe
procedures for preparing various formulations suitable for
administering the compounds according to the invention. Examples of
potential formulations and preparations are contained, for example,
in the Handbook of Pharmaceutical Excipients, American
Pharmaceutical Association (current edition); Pharmaceutical Dosage
Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current
edition, published by Marcel Dekker, Inc., as well as Remington's
Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current
edition).
[0437] Administration of the compounds of the present invention may
be accomplished according to patient needs, for example, orally,
nasally, parenterally (subcutaneously, intraveneously,
intramuscularly, intrasternally and by infusion) by inhalation,
rectally, vaginally, topically and by ocular administration.
[0438] Various solid oral dosage forms can be used for
administering compounds of the invention including such solid forms
as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk
powders. The compounds of the present invention can be administered
alone or combined with various pharmaceutically acceptable
carriers, diluents (such as sucrose, mannitol, lactose, starches)
and excipients known in the art, including but not limited to
suspending agents, solubilizers, buffering agents, binders,
disintegrants, preservatives, colorants, flavorants, lubricants and
the like. Time release capsules, tablets and gels are also
advantageous in administering the compounds of the present
invention.
[0439] Various liquid oral dosage forms can also be used for
administering compounds of the inventions, including aqueous and
non-aqueous solutions, emulsions, suspensions, syrups, and elixirs.
Such dosage forms can also contain suitable inert diluents known in
the art such as water and suitable excipients known in the art such
as preservatives, wetting agents, sweeteners, flavorants, as well
as agents for emulsifying and/or suspending the compounds of the
invention. The compounds of the present invention may be injected,
for example, intravenously, in the form of an isotonic sterile
solution. Other preparations are also possible.
[0440] Suppositories for rectal administration of the compounds of
the present invention can be prepared by mixing the compound with a
suitable excipient such as cocoa butter, salicylates and
polyethylene glycols. Formulations for vaginal administration can
be in the form of a pessary, tampon, cream, gel, past foam, or
spray formula containing, in addition to the active ingredient,
such suitable carriers as are known in the art.
[0441] For topical administration the pharmaceutical composition
can be in the form of creams, ointments, liniments, lotions,
emulsions, suspensions, gels, solutions, pastes, powders, sprays,
and drops suitable for administration to the skin, eye, ear or
nose. Topical administration may also involve transdermal
administration via means such as transdermal patches.
[0442] Aerosol formulations suitable for administering via
inhalation also can be made. For example, the compounds of formulas
I, II, III or IV can be administered by inhalation in the form of a
powder (e.g., micronized) or in the form of atomized solutions or
suspensions. The aerosol formulation can be placed into a
pressurized acceptable propellant.
Methods of Treatment
[0443] The compounds of formulas I, II, III or IV may be useful as
ligands for CC chemokine receptors, for example, CCR1. Therefore,
compounds of formulas I, II, III or IV may be useful in the
treatment of conditions mediated by CC chemokine receptors, for
example, CCR1. In certain embodiments, the compounds of the present
invention may be useful in the treatment of conditions that respond
to a CCR1 receptor agonist, inverse agonist or antagonist. For
example, conditions that respond to a CCR1 antagonist.
[0444] In yet another aspect, the present invention provides
methods of treating CC chemokine receptor (e.g., CCR1) mediated
conditions or diseases by administering to a patient having such a
disease or condition, a therapeutically effective amount of a
compound of formulas I, II, III or IV above.
[0445] CCR1 provides a target for interfering with or promoting
specific aspects of immune cell functions, or more generally, with
functions associated with CCR1 expression on a wide range of cell
types in a mammal, such as a human. Compounds that inhibit CCR1,
are particularly useful for modulating monocyte, macrophage,
lymphocyte, granulocyte, NK cell, mast cells, dendritic cell,
neutrophils, and certain immune derived cell (for example,
osteoclasts) function for therapeutic purposes. Accordingly, the
present invention is directed to compounds which are useful in the
prevention and/or treatment of a wide variety of inflammatory and
immunoregulatory disorders and diseases (see Saeki, et al., Current
Pharmaceutical Design, 9, 1201-1208, 2003).
[0446] There are also provided, in accordance with embodiments of
the invention, methods of treating or preventing inflammatory or
autoimmune diseases comprising administering a compound of formulas
I, II, III or IV. In some embodiments the inflammatory disease or
autoimmune disease is rheumatoid arthritis or multiple
sclerosis.
[0447] Compounds of the genera are CCR1 antagonists. As such, they
have utility in treating and preventing autoimmune disease and
inflammatory diseases. In particular, CCR1 antagonists are
therapeutic targets for the treatment and prevention of a variety
of diseases, including, but not limited to, autoimmune diseases
(such as rheumatoid arthritis, Takayasu arthritis, psoriatic
arthritis, ankylosing spondylitis, type 1 diabetes (recent onset),
lupus, inflammatory bowel disease, Crohn's disease, optic neuritis,
psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis,
thyroiditis and vasculitis); fibrosis (e.g. pulmonary fibrosis
(i.e. idiopathic pulmonary fibrosis, interstitial pulmonary
fibrosis), fibrosis associated with end-stage renal disease,
fibrosis caused by radiation, tubulo interstitial fibrosis,
subepithelial fibrosis, scleroderma (progressive systemic
sclerosis), hepatic fibrosis (including that caused by alcoholic or
viral hepatitis), primary and secondary biliary cirrhosis);
diabetic nephropathy; allergic conditions (such as asthma, contact
dermatitis and atopic dermatitis); acute and chronic lung
inflammation (such as chronic bronchitis, chronic obstructive
pulmonary disease, adult Respiratory Distress Syndrome, Respiratory
Distress Syndrome of infancy, immune complex alveolitis);
atherosclerosis; vascular inflammation resulting from tissue
transplant or during restenosis (including, but not limited to
restenosis following angioplasty and/or stent insertion); other
acute and chronic inflammatory conditions (such as synovial
inflammation caused by arthroscopy, hyperuremia, or trauma,
osteoarthritis, ischemia reperfusion injury, glomerulonephritis,
nasal polyosis, enteritis, Behcet's disease, preeclampsia, oral
lichen planus, Guillian-Barre syndrome); acute and/or chronic
transplant rejection (including xenotransplantation); HIV
Infectivity (co-receptor usage); granulomatous diseases (including
sarcoidosis, leprosy and tuberculosis); conditions associated with
leptin production (such as obesity, cachexia, anorexia, type II
diabetes, hyperlipidemia and hypergonadism); Alzheimer's disease
and other neurodegenerative diseases; osteolytic lesion and
sequelae associated with certain cancers such as multiple myeloma;
diagnosis and treatment of endometriosis; analgesia. Compounds of
formulas I, II, III or IV may also inhibit the production of
metallo proteinases and cytokines at inflammatory sites (including
but not limited to MMP9, TNF, IL-I, and IL-6) either directly or
indirectly (as a consequence of decreasing cell infiltration) thus
providing benefit for diseases or conditions linked to these
cytokines (such as joint tissue damage, hyperplasia, pannus
formation and bone resorption, hepatic failure, Kawasaki syndrome,
myocardial infarction, acute liver failure, septic shock,
congestive heart failure, pulmonary emphysema or dyspnea associated
therewith). Compounds of formulas I, II, III or IV may also prevent
tissue damage caused by inflammation induced by infectious agents
(such as viral induced encephalomyelitis or demyelination, viral
inflammation of the lung or liver (e.g. caused by influenza or
hepatitis or respiratory syncytial virus), gastrointestinal
inflammation (for example, resulting from H. pylori infection),
inflammation resulting from: bacterial meningitis, HIV-1, HIV-2,
HIV-3, cytomegalovirus (CMV), adenoviruses, Herpes viruses (Herpes
zoster and Herpes simplex) fungal meningitis, lyme disease,
malaria), arterial remodeling characterized by neointima formation
and medial thickening for mediating inflammatory cell recruitment
and endothelial dysfunction.
[0448] There are also provided, in accordance with additional
embodiments of the invention, methods of treating or preventing a
disease disease or condition selected from, for example,
hepatocellular carcinoma, respiratory synctial virus (RSV), kidney
disease, allergic asthma, Alport disease (which includes
glumerulosclerosis and progressive renal fibrosis), prion diseases,
sepsis, T-cell mediated liver diseases, severe respiratory viruses,
chronic renal injury, and transplant and cardio allograft
vascalopathy (chronic rejection) comprising administering a
compound of formulas I, II, III or IV. In some embodiments the
Alport disease is renal fibrosis.
[0449] There are also provided, in accordance with embodiments of
the invention, methods of treating or preventing endometriosis
comprising administering a compound of formulas I, II, III or
IV.
[0450] In certain embodiments, the compounds of the invention are
useful in the treatment of elevated levels of lipids,
cardiovascular diseases, diabetes, obesity, and metabolic
syndrome.
[0451] In the treatment or prevention of conditions which require
chemokine receptor modulation an appropriate dosage level will
generally be about 0.001 to 100 mg per kg patient body weight per
day which can be administered in single or multiple doses. For
example, the dosage level will be about 0.01 to about 25 mg/kg per
day; such as about 0.05 to about 10 mg/kg per day. A suitable
dosage level may be about 0.01 to 25 mg/kg per day, about 0.05 to
10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within this
range the dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0
mg/kg per day. For oral administration, the compositions may be
provided in the form of tablets containing about 1 to about 1000
milligrams of the active ingredient, such as about 1, about 5,
about 10, about 15, about 20, about 25, about 50, about 75, about
100, about 150, about 200, about 250, about 300, about 400, about
500, about 600, about 750, about 800, about 900, and about 1000
milligrams of the active ingredient. The compounds may be
administered on a regimen of 1 to 4 times per day, for example,
once or twice per day.
[0452] It will be understood, however, that the specific dose level
and frequency of dosage for any particular patient may be varied
and will depend upon a variety of factors including the activity of
the specific compound employed, the metabolic stability and length
of action of that compound, the age, body weight, hereditary
characteristics, general health, sex and diet of the subject, as
well as the mode and time of administration, rate of excretion,
drug combination, and the severity of the particular condition for
the subject undergoing therapy.
[0453] The compounds and compositions of the present invention can
be combined with other compounds and compositions having related
utilities to prevent and treat the conditions described herein,
such as, for example, inflammatory or autoimmune disorders,
conditions and diseases, including inflammatory bowel disease,
rheumatoid arthritis, osteoarthritis, psoriatic arthritis,
polyarticular arthritis, multiple sclerosis, allergic diseases,
psoriasis, atopic dermatitis and asthma.
[0454] For example, in the treatment or prevention of inflammation
or autimmunity or for example arthritis associated bone loss, the
present compounds and compositions may be used in conjunction with,
for example, an anti-inflammatory or analgesic agent such as an
opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of
5-lipoxygenase, a cyclooxygenase inhibitor, such as a
cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an
interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric
oxide or an inhibitor of the synthesis of nitric oxide, a non
steroidal anti-inflammatory agent, or a cytokine-suppressing
anti-inflammatory agent, for example with a compound such as
acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin,
ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal
analgesic, sufentanyl, sunlindac, tenidap, and the like. Similarly,
the instant compounds and compositions may be administered with an
analgesic listed above; a potentiator such as caffeine, an H2
antagonist (e.g., ranitidine), simethicone, aluminum or magnesium
hydroxide; a decongestant such as phenylephrine,
phenylpropanolamine, pseudoephedrine, oxymetazoline, ephinephrine,
naphazoline, xylometazoline, propylhexedrine, or levo desoxy
ephedrine; an antitussive such as codeine, hydrocodone, caramiphen,
carbetapentane, or dextromethorphan; a diuretic; and a sedating or
non sedating antihistamine.
[0455] Such other drug(s) may be administered, by a route and in an
amount commonly used therefor, contemporaneously or sequentially
with a compound of formulas I, II, III or IV. When a compound of
formulas I, II, III or IV is used contemporaneously with one or
more other drugs, a pharmaceutical unit dosage form containing such
other drugs in addition to the compound of formulas I, II, III or
IV may be employed. Accordingly, the pharmaceutical compositions of
the present invention include those that also contain one or more
other active ingredients, in addition to a compound of formulas I,
II, III or IV.
[0456] The term "treating" means to relieve, alleviate, delay,
reduce, reverse, improve or prevent at least one symptom of a
condition in a subject. The term "treating" may also mean to
arrest, delay the onset (i.e., the period prior to clinical
manifestation of a disease) and/or reduce the risk of developing or
worsening a condition.
[0457] An "effective amount" means the amount of a compound of
formulas I, II, III or IV that, when administered to a patient
(e.g., a mammal) for treating a disease, is sufficient to effect
such treatment for the disease to achieve the objectives of the
invention. The "effective amount" will vary depending on the
compound, the disease and its severity and the age, weight, etc.,
of the patient to be treated.
[0458] A subject or patient in whom administration of the
therapeutic compound is an effective therapeutic regimen for a
disease or disorder is preferably a human, but can be any animal,
including a laboratory animal in the context of a clinical trial or
screening or activity experiment. Thus, as can be readily
appreciated by one of ordinary skill in the art, the methods,
compounds and compositions of the present invention are
particularly suited to administration to any animal, particularly a
mammal, and including, but by no means limited to, humans, domestic
animals, such as feline or canine subjects, farm animals, such as
but not limited to bovine, equine, caprine, ovine, and porcine
subjects, wild animals (whether in the wild or in a zoological
garden), research animals, such as mice, rats, rabbits, goats,
sheep, pigs, dogs, cats, etc., avian species, such as chickens,
turkeys, songbirds, etc., i.e., for veterinary medical use.
[0459] The term "about" or "approximately" means within an
acceptable error range for the particular value as determined by
one of ordinary skill in the art, which will depend in part on how
the value is measured or determined, i.e., the limitations of the
measurement system. For example, "about" can mean within 1 or more
than 1 standard deviations, per practice in the art. Alternatively,
"about" with respect to the compositions can mean plus or minus a
range of up to 20%, such as up to 10%, for example, up to 5%.
Examples
[0460] The present invention will now be further described by way
of the following non-limiting examples. In applying the disclosure
of these examples, it should be kept clearly in mind that other and
different embodiments of the methods and synthetic schemes
disclosed according to the present invention will no doubt suggest
themselves to those of skill in the relevant art.
[0461] In the foregoing and in the following examples, all
temperatures are set forth uncorrected in degrees Celsius; and,
unless otherwise indicated, all parts and percentages are by
weight.
[0462] The following abbreviations may be used herein: Ac
(CH.sub.3CO), Bn (benzyl), DCM (dichloromethane), DMF
(dimethylformamide), DIPEA (N,N-diisopropyl ethyl amine), EDCI
(1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride), Et
(ethyl), HOBT (1-hydroxybenzotriazole), Me (methyl), TFA
(trifluoroacetic acid), THF (tetrahydrofuran), EtOH (ethanol),
EtOAc (ethyl acetate), MeOH (methanol), K.sub.2CO.sub.3 (potassium
carbonate), Pd/C (palladium on carbon), Boc (tert-butoxycarbonyl),
Na.sub.2SO.sub.4 (sodium sulphate), CHCl.sub.3 (chloroform), NaOH
(sodium hydroxide), DMAP (dimethyl amino pyridine), NMR (nuclear
magnetic resonance), DMSO-d.sub.6 (deuterated dimethyl sulfoxide),
CDCl.sub.3 (deuterated chloroform), LC-MS (liquid
chromatography-mass spectrometry), LDA (lithium diisopropylamine),
HPLC (high pressure liquid chromatography or high performance
liquid chromatography), Me.sub.2NH (dimethyalamine) RT (room
temperature), Nall (sodium hydride), tBuOK (potassiume
tert-butoxide), NH.sub.4Cl (ammonium chloride), LiOH (lithium
hydroxide), H.sub.2O.sub.2 (hydrogen peroxide), NaHCO.sub.3 (sodium
hydrogen carbonate), DMS (dimethyl sulfoxide), GCMS (gas
chromatography-mass spectrometry), Si-gel (silica gel),
Na.sub.2S.sub.2O.sub.4 (sodium hydrosulfite), TBTU
(O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate), Jones Reagent (chromium trioxide in aqueous
sulfuric acid).
Example 1
(6-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[(R)-4-(4-fluoro-benzyl)-2-me-
thyl-piperazin-1-yl]-methanone
##STR00017## ##STR00018##
[0463] Preparation of
(R)-1-(4-fluoro-benzyl)-3-methyl-piperazine
[0464] A mixture of (R)-2-Methyl-piperazine (2 g, 0.02 mol),
4-fluorobenzyl bromide (2.38 ml, 0.02 mol), and sodium bicarbonate
(5.04 g, 0.06 mol) in ethanol was refluxed for 24 hours. The
solution was filtered and the filtrate was evaporated under reduced
pressure. The residue was diluted with water and extracted with
ethyl acetate. The organic layer was washed with brine solution and
dried over sodium sulfate. The crude was purified over neutral
alumina (5% ethyl acetate-hexane) to afford 1.2 g (29%) of
(R)-1-(4-fluoro-benzyl)-3-methyl-piperazine. LC/MS [M+H.sup.+:
209.3. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 7.27-6.96
(m, 4 Ar--H,), 3.43 (s, 2H), 2.96-2.82 (m, 3H)), 2.73 (d, J=11.5
Hz, 2H), 2.00 (m, 1H), 1.65 (m, 1H), 1.00 (d, J=6.6 Hz, 3H).
Step-1: 2-Benzyloxy-5-chloro-benzaldehyde
[0465] To a solution of 5-Chloro-2-hydroxy-benzaldehyde (1 g, 6.4
mmol) in THF was added potassium tert- butoxide (788 mg, 7 mmol)
portion wise at 0.degree. C. and stirred at room temperature for 2
h. Benzyl bromide (0.76 ml, 6.4 mmol) was added to the reaction
solution at 0.degree. C. and refluxed for 4 h. The reaction mixture
was concentrated, diluted with water, and the product was extracted
with ethyl acetate. Concentration of ethyl acetate layer in vacuo
afforded 1.6 g (99%) of 2-Benzyloxy-5-chloro-benzaldehyde. GCMS
[m/z]:246.0. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm):
10.34 (s, 1H), 7.72-7.33 (m, 8 Ar H), 5.31 (s, 2H),
Step-2: 2-benzyloxy-5-chlorophenol
[0466] 2-Benzyloxy-5-chloro-benzaldehyde (200 mg, 0.81 mmol) was
dissolved in methanol and treated with hydrogen peroxide (0.36 ml,
30%) and conc. sulfuric acid (0.17 ml). The mixture was stirred
overnight at room temperature and evaporated. The residue was
dissolved in saturated aq. NaCl solution and extracted with ether.
The organic phase was dried over sodium sulfate and concentrated
under reduced pressure. Purification of the residue by flash
chromatography (silica-gel, 2% EtOAc-hexane) afforded 85 mg (45%)
of 2-benzyloxy-5-chlorophenol. GCMS [m/z]:234.
[0467] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 9.56 (s,
1H), 7.46-6.72 (m, 8 Ar H), 5.09 (s, 2H).
Step-3: 2-(2-Benzyloxy-5-chloro-phenoxymethyl)-oxirane
[0468] 2-benzyloxy-5-chlorophenol 2 (200 mg, 8.5 mmol) was
dissolved in DMF and treated with epi-chlorohydrine (118 mg, 1.3
mmol) using a catalytic amount of KI and cesium carbonate (415 mg,
1.3 mmol). The mixture was stirred at room temperature for 24 h.
The reaction mixture was diluted with water, extracted with ether,
and the organic layer was dried over Na.sub.2SO.sub.4 and finally
concentrated under reduce pressure to afford 250 mg (99%) of
2-(2-benzyloxy-5-chloro-phenoxymethyl)-oxirane. GCMS [m/z]: 290.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 7.42-6.8 (m, 8 Ar
H), 5.08 (s, 2H), 4.26 (dd, J=8.24, 3.04 Hz 1H), 3.98 (m, 1H), 3.35
(m, 1H), 2.88 (m, 1H), 2.75 (m, 1H).
Step-4: 4-Chloro-2-oxiranylmethoxy-phenol
[0469] 2-(2-Benzyloxy-5-chloro-phenoxymethyl)-oxirane (100 mg, 3.4
mmol) was hydrogenated with 5% Pd-C (40 mg) in ethyl acetate for
1.5 h. The catalyst was filtered through a celite bed.
Concentration of the ethyl acetate solution afforded 50 mg (99%) of
4-chloro-2-oxiranylmethoxy-phenol. GCMS [m/z]: 200. .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. (ppm): 6.93-6.81 (m, 3 Ar H), 4.30
(dd, J=3.8, 2.4 Hz, 1H), 4.0 (m, 1H), 3.36 (m, 1H), 2.95 (t, J=4.4
Hz, 1H), 2.82 (m, 1H).
Step-5: (6-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol
[0470] 4-Chloro-2-oxiranylmethoxy-phenol (500 mg, 2.5 mmol) was
dissolved in ethanol and treated with 2.6 ml of aq. 1(N) NaOH
solution. The mixture was stirred for 30 min. and diluted with
ether. The organic phase was washed with 1(N) HCl solution and
water, dried over sodium sulfate and concentrated to afford 420 mg
(70%) of (6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol.
.sup.1H-NMR (400 MHz, CDCl.sub.3), .delta. (ppm): 6.93-6.82 (m, 3
Ar H), 4.27 (dd, J=9.1, 2.2 Hz, 1H), 4.21 (m, 1H), 4.08 (m, 1H),
3.89 (dd, J=7.89, 4.1 Hz, 1H), 3.8 (m, 1H).
Step-6: 6-Chloro-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic
acid
[0471] To a stirred solution of
(6-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol (420 mg, 2.1
mmol) in acetone was added Jones reagent (1.35 ml) dropwise at
10-15.degree. C. The reaction was stirred at room temperature for
3.5 h and then was diluted with chloroform. The organic layer was
separated and evaporated. The residue was taken up in chloroform
and was washed with saturated sodium bicarbonate solution. The
aqueous phase was washed with chloroform, cooled, acidified with
conc. HCl (pH 1) and was extracted with chloroform. Concentration
of the chloroform layer afforded 105 mg (23%) of
6-Chloro-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid. GCMS
[m/z]: 214. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm):
13.46 (br s, 1H), 6.96 (m, 2H), 6.9 (dd, J=6.3, 2.4 Hz, 1H), 5.08
(t, J=2.9 Hz, 1H), 4.30 (dd, J=8.9, 3.2 Hz, 1H), 4.27 (dd, J=8.5,
2.8 Hz, 1H).
Step-7:
(6-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[(R)-4-(4-fluoro-ben-
zyl)-2-methyl-piperazin-1-yl]-methanone
[0472] To a solution of
6-chloro-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (500 mg,
2.3 mmol) in DMF was added
(R)-1-(4-fluoro-benzyl)-3-methyl-piperazine (487 mg, 2.35 mmol),
TBTU (827 mg, 2.6 mmol), and DIPEA (0.4 ml) at 5-10.degree. C. and
the resulting mixture was stirred at room temperature for 14-16
hours. The reaction mixture was diluted with water and the product
was extracted with ethyl acetate. The ethyl acetate layer was
concentrated in vacuo and subjected to column chromatography (45%
ethyl acetate-hexane) to afford 450 mg (48%) of
(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[(R)-4-(4-fluoro-benzyl)-2-m-
ethyl-piperazin-1-yl]hmethanone. LC/MS [M+H].sup.+: 405.2.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.35 (t, J=5.8
Hz, 2H), 7.16 (t, J=8.8 Hz, 2H), 6.88 (m, 3H), 5.21 (m, 1H),
4.47-3.79 (m, 7H), 2.91-1.87 (m, 5H), 1.18 (d, J=12.2 Hz, 3H). HPLC
purity: 95.1%
Example 2
(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-[(R)-4-(4-fluoro-benzyl)-2-methyl-pipe-
razin-1-yl]-methanone
##STR00019##
[0474]
(6-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[(R)-4-(4-fluoro-benzy-
l)-2-methyl-piperazin-1-yl]-methanone (40.5 mg, 0.1 mmol) was
hydrogenated with 10% Pd-C catalyst for 14 hours. The catalyst was
removed by filtration through a celite bed. Concentration of the
ethanol solution afforded 35 mg (85%) of
(2,3-dihydro-benzo[1,4]dioxin-2-yl)-[(R)-4-(4-fluoro-benzyl)-2-methyl-pip-
erazin-1-yl]-methanone. LC/MS [M+H].sup.+: 371.4. .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. (ppm): 7.36 (t, 2H), 7.16 (t, 2H), 6.88
(m, 4H), 5.15 (m, 1H) 4.48 (m, 1H), 4.38 (m, 1H)), 4.15 (m, 2H),
3.38 (m, 1H), 2.78 (m, 1H), 2.60 (m, 2H), 2.02 (m, 1H), 1.39 (d,
1H), 1.33 (m, 1H), 1.23 (m, 1H), 1.16 (t, 2H). HPLC purity:
97.1%
Example 3
(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-[4-(4-fluoro-benzyl)-piperazin-1-yl]-m-
ethanone
##STR00020##
[0476]
(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-[4-(4-fluoro-benzyl)-piperazin--
1-yl]-methanone was prepared from
(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[4-(4-fluoro-benzyl)-piperaz-
in-1-yl]hmethanone by a process similar to that described in
Example 2. LC/MS [M+H].sup.+: 357.2. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 7.27 (m, 2H), 7.03 (t, 2H), 6.86 (m,
4H), 4.81 (dd, 1H), 4.48 (dd, 1H), 4.30 (m, 1H), 3.74 (m, 2H), 3.57
(m, 2H), 3.49 (s, 2H0, 2.44 (m, 4H). HPLC purity: 94.3%.
Example 4
(6-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[4-(4-fluoro-benzyl)-piperazi-
n-1-yl]-methanone
##STR00021##
[0477] Preparation of 1-(4-Fluoro-benzyl)-piperazine
[0478] To a solution of 1-boc-piperazine (1 g, 5.4 mmol) in THF was
added 4-fluorobenzyl bromide (0.7 ml, 5.4 mmol) and triethylamine
(2.2 ml, 16.1 mmol). The reaction mixture was stirred for 22 hour
at room temperature. The reaction mixture was concentrated, diluted
with water and the product extracted with ethyl acetate. The
organic layer was washed with water and dried over sodium sulfate.
The organic solution was concentrated to afford 1.6 g (100%) of
4-(4-fluoro-benzyl)-piperazine-1-carboxylic acid tert-butyl
ester.
[0479] To a solution of 4-(4-fluoro-benzyl)-piperazine-1-carboxylic
acid tert-butyl ester (1.6 g, 5.4 mmol) in DCM was added
trifluoroacetic acid (4.16 ml, 54 mmol). The resulting mixture was
stirred for about 5 h. The reaction mass was concentrated and the
residue was washed with dry ether. The TFA salt was diluted with
minimum volume of water and neutralized with aq. NaOH solution at
5-10.degree. C. Extraction of the aqueous solution with ethyl
acetate followed by concentration of the combined organic phases
under reduced pressure afforded 1 g (95%) of
1-(4-Fluoro-benzyl)-piperazine. LC/MS [M+H]: 195.2. .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.33-7.10 (m, 4 Ar H), 3.4
(s, 2H), 2.70 (t, J=4.8 Hz, 4H), 2.30 (t, J=1.6 Hz, 4 H).
[0480]
(6-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[4-(4-fluoro-benzyl)-p-
iperazin-1-yl]-methanone was prepared by a process similar to that
described in Example 1. LC/MS [M+H].sup.+: 391.2. .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. (ppm): 7.27 (m, 2H), 2.00 (m, 2H), 6.89
(br s, 1H), 6.81 (m, 2H), 4.79 (m, 1H), 4.46 (dd, 1H), 4.29 (m,
1H), 3.71 (m, 2H), 3.55 (m, 2H), 3.48 (m, 2H), 2.43 (m, 4H). HPLC
purity: 98.1%
Example 5
(6-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[4-(4-fluoro-benzyl)-[1,4]dia-
zepan-1-yl]-methanone
##STR00022##
[0482] 1-(4-Fluoro-benzyl)-[1,4]diazepane was prepared from
1-Boc-[1,4]diazapane using a procedure similar to that described
for 1-(4-fluoro-benzyl)-piperazine in Example 4.
[0483] To a solution of
6-chloro-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (as
described above in example 1) (97 mg, 0.47 mmol) DMF was added
1-(4-Fluoro-benzyl)-[1,4]diazepane (100 mg, 0.47 mmol), EDCI (116
mg, 0.61 mmol), HOBt (31 mg, 0.24 mmol) and DIPEA (0.23 ml, 1.4
mmol) at 5-10.degree. C. and was stirred the reaction mixture at
room temperature for 14-16 hours. The reaction mixture was diluted
with water and extracted with ethyl acetate. The ethyl acetate
solution was concentrated in vacuo and subjected to column
chromatography (45% ethyl acetate-hexane) to afford 45 mg (24%) of
(6-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[4-(4-fluoro-benzyl)-[1,4]di-
azepan-1-yl]-methanone. LC/MS [M+H].sup.+: 405.0. .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. (ppm): 7.37-6.88 (7 Ar H), 5.20 (m, 1H),
4.38 (m, 1H), 4.20 (m, 1H), 3.74-3.36 (m, 6H), 2.71 (m, 1H), 2.57
(m, 3H), 1.84 (m, 1H), 1.73 (m, 1H). HPLC purity: 94.3%
Example 6
(6,7-Dichloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[(R)-4-(4-fluoro-benzyl)--
2-methyl-piperazin-1-yl]-methanone
##STR00023##
[0484] Step 1:
6,7-Dichloro-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid ethyl
ester
[0485] A mixture of 4,5-dichlorocatechol (250 mg, 1.4 mmol) was
refluxed with ethyl-1,2-dibromopropionate (363 mg, 1.4 mmol) in
acetone with potassium carbonate (290 mg, 2.1 mmol) for 9 h. The
reaction mixture was concentrated and extracted with ethyl acetate.
The ethyl acetate layer was concentrated and the crude product was
subjected to column chromatography (silica gel, 5% ethyl
acetate-hexane) to afford 310 mg (81%) of
6,7-Dichloro-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid ethyl
ester. LC/MS [M+H].sup.+: 277.1. .sup.1H-NMR (400 MHz, CDCl3)
.delta. (ppm): 7.09 (s, 1H), 6.96 (s, 1H), 4.81 (m, 1H), 4.42 (m,
1H), 4.28 (m, 1H), 4.25 (q, 2H), 1.28 (t, 3H).
Step 2: 6,7-Dichloro-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic
acid
[0486] To a solution of
6,7-Dichloro-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid ethyl
ester (310 mg, 1.12 mmol) in THF: H.sub.2O (2:1) was added LiOH (61
mg, 1.45 mmol) and the resulting mixture was stirred for 3 hours.
The reaction mixture was then concentrated and the crude mass was
neutralized with 6(N) HCl solution and extracted with ethyl
acetate. Concentration of the ethyl acetate layer afforded 210 mg
(71.4%) of 6,7-Dichloro-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic
acid. .sup.1H-NMR (400 MHz, CDCl3) .delta. (ppm): 7.29-6.93 (2Ar
H), 4.66 (m, 1H), 4.35 (m, 1H ), 4.12 (m, 1H).
Step 3:
(6,7-Dichloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[(R)-4-(4-fluoro-
-benzyl)-2-methyl-piperazin-1-yl]-methanone
[0487] To a solution of
6,7-Dichloro-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (100
mg, 0.48 mmol) in dichloromethane was added
(R)-1-(4-fluoro-benzyl)-3-methyl-piperazine (119.6 mg, 0.48 mmol),
EDCI (119.4 mg, 0.62 mmol), HOBt (32.4 mg, 0.24 mmol) and DIPEA
(0.25 ml, 1.44 mmol) at 5-10.degree. C. and the reaction mixture
was stirred at room temperature for 14-16 hours. The mixture was
diluted with water and extracted with ethyl acetate. The ethyl
acetate layer was concentrated in vacuo and subjected to column
chromatography (45% ethyl acetate-hexane) to afford 25 mg (11.8%)
of
(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[(R)-4-(4-fluoro-benzyl)-
-2-methyl-piperazin-1-yl]-methanone. LC/MS [M+H].sup.+: 439.0.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.3-6.98 (m,
6H), 4.73 (m, 2H), 4.46 (m, 1H), 4.29 (m, 2H), 4.11 (m, 1H), 3.51
(m, 1H), 3.43 (m, 1H), 2.84 (m, 1H), 2.68 (m, 1H), 2.16 (m, 1H),
2.05 (m, 1H), 1.52 (m, 1H), 1.39 (d, 1H), 1.28 (m, 1H). HPLC
purity: 94.9%
Example 7
(6,7-Dichloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[4-(4-fluoro-benzyl)-[1,4-
]diazepan-1-yl]-methanone
##STR00024##
[0489]
(6,7-Dichloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[4-(4-fluoro-benzy-
l)-[1,4]diazepan-1-yl]-methanone was prepared by a process similar
to that described in Example 6. LC/MS [M+H].sup.+: 439.3.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.37-7.11 (m,
6H), 5.29 (m, 1H), 4.38 (m, 1H), 4.28 (m, 1H), 4.03-1.71 (m, 12H).
HPLC purity: 89.6%
Example 8
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[(R)-4-(4-fluoro-benzyl)-2-
-methyl-piperazin-2-yl]-methanone
##STR00025##
[0490] Step-1:
6-Chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic acid
4-tert-butyl ester 2-ethyl ester
[0491] To a solution of
ethyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylate (Key
Organics, UK) (500 mg, 2.1 mmol) in THF was added DMAP (50 mg, 5.1
mmol) and di-tert-butyl dicarbonate (0.7 ml, 3.1 mmol). The
solution was stirred for 18 h. The reaction mixture was
concentrated. The crude mass was diluted with water and extracted
with ethyl acetate. Concentration of ethyl acetate solution
afforded 160 mg (100%) of
6-Chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic acid
4-tert-butyl ester 2-ethyl ester. LC/MS [M+H].sup.+: .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.71 (br s, 1H), 7.08-6.97 2
Ar H), 5.21 (t, J=3.1 Hz, 1H), 4.41 (m, 1H), 4.11 (m, 1H), 3.56
(dd, J=11.0, 2.9 Hz, 1H), 1.38 (s, 9H), 1.17 (t, J=7.0 Hz, 3H).
Step-2: 6-Chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester
[0492] To a solution of
ethyl6-Chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic acid
4-tert-butyl ester 2-ethyl ester (302 mg, 0.88 mmol) in THF:
H.sub.2O (2:1) was added lithium hydroxide (74.9 mg, 1.77 mmol).
The reaction mixture was stirred for 5-6 h then concentrated. The
crude mass was neutralized with 50% aqueous acetic acid and
extracted with ethyl acetate. Concentration of the ethyl acetate
layer afforded 270 mg (97%) of
6-Chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic acid
4-tert-butyl ester. GCMS [m/z-Boc]: 213. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm):13.40 (br s, 1H), 7.72-6.95 (3 Ar H),
5.06 (br, s, 1H), 4.40 (dd, J=11.2, 2.6 Hz, 1H), 3.55 (dd, J=10.8,
3.0 Hz, 1H), 1.38 (s, 9H)
Step-3:
6-Chloro-2-[(R)-4-(4-fluoro-benzyl)-2-methyl-piperazine-1-carbony-
l]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester
[0493] To a solution of
6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic acid
4-tert-butyl ester (415 mg, 1.3 mmol) in DMF was added
(R)-1-(4-fluoro-benzyl)-3-methyl-piperazine (257 mg, 1.3 mmol)),
EDCI (330 mg, 1.7 mmol), HOBt (89 mg, 0.7 mmol) and DIPEA (0.7 ml,
3.9 mmol) at 5-10.degree. C. The reaction mixture was stirred at
room temperature for 14-16 then diluted with water and extracted
with ethyl acetate. The ethyl acetate layer was concentrated in
vacuo and subjected to column chromatography (Si-gel, 45% ethyl
acetate-hexane) to afford 197 mg (30%) of
6-chloro-2-[(R)-4-(4-fluoro-benzyl)-2-methyl-piperazine-1-carbonyl]-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester.
LC/MS [M+H].sup.+: 504.4
Step-4:
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[(R)-4-(4-fluoro--
benzyl)-2methyl-piperazin-1-yl]-methanone
[0494] To a solution of
6-chloro-2-[(R)-4-(4-fluoro-benzyl)-2-methyl-piperazine-1-carbonyl]-2,3-d-
ihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (190
mg, 0.37 mmol) in DCM was added trifluoroacetic acid (0.3 ml, 3.9
mmol). The reaction mixture was stirred for about 5 hours then
concentrated and washed with dry ether. The TFA salt was diluted
with a minimum volume of water and neutralized with aq. NaOH
solution at 5-10.degree. C. Extraction of the neutralized solution
followed by concentration afforded 114 mg (75%) of
(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[(R)-4-(4-fluoro-benzyl)--
2-methyl-piperazin-1-yl]-methanone. LC/MS [M+H].sup.+: 404.2
.sup.1H-NMR VT 90.degree. C. (400 MHz, DMSO-d.sub.6) .delta. (ppm):
7.35 (m, 2H), 7.12 (m, 2H), 6.67 (m, 1H), 6.62 (d, J=2.4 Hz, 1H),
6.46 (m, 1H), 5.84 (br s, 1H), 4.80 (m, 1H), 4.45 (m, 1H), 3.96 (m,
1H), 3.53-3.21 (m, 5H), 2.80 (m, 1H), 2.65 (m, 1H), 2.16 (m, 1H),
2.03 (m, 1H), 1.25 (d, J=6.7 Hz, 3H), HPLC purity: 99.7%.
Example 9
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-benzyl)-piper-
azin-1-yl]-methanone
##STR00026##
[0496]
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-benzyl-
)-piperazin-1-yl]-methanone was prepared by a process similar to
that described in Example 8. LC/MS [M+H].sup.+: 390.3. .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.35 (m, 2H), 7.15 (t, J=8.8
Hz, 2H), 6.67 (d, J=8.4 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H), 6.46 (dd,
J=6.0, 2.4 Hz, 1H), 6.17 (s, 1H), 4.89 (m, 1H), 3.57-3.38 (br m,
7H), 2.66 (m, 1H), 2.40-2.32 (m, 4H). HPLC purity: 80.9%
Example 10
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-benzyl)-[1,4]-
diazepan-1-yl]-methanone
##STR00027##
[0498]
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-benzyl-
)-[1,4]diazepan-1yl]-methanone was prepared by a process similar to
that described in Example 8. LC/MS [M+H].sup.+: 404.3. .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.34 (m, 2H), 7.13 (m, 2H),
6.70-6.58 (m, 2H), 6.45 (m, 1H), 6.18 (s, 1H), 4.83 (m, 1H),
3.67-1.73 (m, 14H). HPLC purity: 81.8%
Example 11
6-Chloro-2-[4-(4-fluoro-benzyl)-[1,4]diazepane-1-carbonyl]-2,3-dihydro-ben-
zo[1,4]oxazine-4-carboxylic acid amide
##STR00028##
[0500] To a solution of
(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-benzyl)-[1,4-
]diazepan-1-yl]-methanone (47 mg, 0.17 mmol) in THF was added
triethylamine (0.03 ml, 0.23 mmol) and ethyl chloroformate (0.01
ml, 0.16 mmol) under ice-cold condition. The reaction mixture was
stirred overnight, then concentrated and extracted with ethyl
acetate. The ethyl acetate layer was concentrated. The concentrated
mass was dissolved in ethanol and condensed with NH.sub.3 at
0.degree. C. in a sealed tube and the solution was heated at
70.degree. C. overnight. The solution was concentrated in vacuo and
subjected to column chromatography (Si-gel, 2% MeOH-DCM) to obtain
11 mg (25%)
6-chloro-2-[4-(4-fluoro-benzyl)-[1,4]diazepane-1-carbonyl]-2,3-dihydro-be-
nzo[1,4]oxazine-4-carboxylic acid amide. LC/MS [M+H]: 446. HPLC
purity: 83.21%
Example 12
(6-Chloro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[(R)-4-(4-fluoro--
benzyl)-2-methyl-piperazin-1-yl]-methanone
##STR00029##
[0502] To a solution of
6-chloro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid (prepared from
6-Chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic acid
4-tert-butyl ester 2-ethyl ester with cesium carbonate and methyl
iodide followed by hydrolysis with lithium hydroxide) (100 mg, 0.44
mmol) in DMF was added 1-(4-fluoro-benzyl)-[1,4]diazepane (100 mg,
0.44 mmol), EDCI (109 mg, 0.57 mmol), HOBt (30 mg, 0.22 mmol) and
DIPEA (0.22 ml, 1.32 mmol) at 5-10.degree. C. The reaction mixture
was stirred at room temperature for 15 hours then diluted with
water and extracted with ethyl acetate. The ethyl acetate layer was
concentrated in vacuo and subjected to column chromatography
(Si-gel, 3% MeOH-DCM) to afford 50 mg (27%) of
(6-chloro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[(R)-4-(4-fluoro-
-benzyl)-2-methyl-piperazin-1-yl]-methanone. LC/MS [M+H].sup.+:
418.1. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.35 (m,
2H), 7.15 (m, 2H), 6.67 (m, 2H), 6.56 (br s, 1H), 5.75 (s, 1H),
5.05 (M, 1H), 4.47-3.30 (m, 7H), 2.89 (s, 3H), 2.78-0.85 (m, 8H).
HPLC purity: 99.4%
Example 13
(6-Chloro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-benz-
yl)-[1,4]diazepan-1-yl]-methanone
##STR00030##
[0504] To a solution of
6-chloro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid (prepared from
6-Chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic acid
4-tert-butyl ester 2-ethyl ester with cesium carbonate and methyl
iodide followed by hydrolysis with lithium hydroxide) (100 mg, 0.44
mmol) in DMF was added 1-(4-fluoro-benzyl)-[1,4]diazepane (100 mg,
0.44 mmol), EDCI (109 mg, 0.57 mmol), HOBt (30 mg, 0.22 mmol) and
DIPEA (0.22 ml, 1.32 mmol) at 5-10.degree. C. The reaction mixture
was stirred at room temperature for 15 hours then diluted with
water and extracted with ethyl acetate. The ethyl acetate layer was
concentrated in vacuo and subjected to column chromatography
(Si-gel, 3% MeOH-DCM) to afford 50 mg (27%) of
(6-chloro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-4-fluoro-benz-
yl)-[1,4]diazepan-1-yl]-methanone. LC/MS [M+H].sup.+: 418.1.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.34 (m, 2H),
7.13 (m, 2H), 6.67 (m, 2H), 6.55 (m, 1H), 5.05 (m, 1H), 3.67 (m,
1H), 3.61 (m, 3H), 3.48 (m, 1H), 3.44 (m, 1H), 3.40 (m, 1H), 2.85
(s, 3H), 2.74 (m, 2H), 2.71 (m, 4H), 1.83 (m, 1H), 1.73 (m, 1H).
HPLC purity: 98.1%
Example 14
6-Chloro-2-[(R)-4-(4-fluoro-benzyl)-2-methyl-piperazine-1-carbonyl]-4H-ben-
zo[1,4]oxazin-3-one
##STR00031##
[0505] Step-1: 2-(4-Chloro-2-nitro-phenoxy)-malonic acid diethyl
ester
[0506] 4-Chloro-2-nitrophenol (1 g, 5.76 mmol) was dissolved in a
minimum volume of DMF, and then anhydrous K.sub.2CO.sub.3 1.6 g
(11.5 mmol) and diethyl-2-bromomalonate 1.08 ml (6.34 mmol) were
added to the solution. The resulting mixture was stirred at room
temperature overnight. The mixture was diluted with ice-water and
extracted with ethyl acetate. The organic layer was washed
successively with water and brine then dried over Na.sub.2SO.sub.4.
The organic layer was concentrated under reduced pressure and the
residue was purified by flash chromatography (silica-gel, 2%
EtOAc-hexane) to afford 600 mg (32%) of
2-(4-Chloro-2-nitro-phenoxy)-malonic acid diethyl ester. LC/MS
[M+H].sup.+: 332.1. .sup.1 H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 8.08 (s, 1H), 7.74 (m, 1H), 7.37 (d, 1H), 4.21 (m, 4H), 5.99
(s, 1H), 1.20 (t, 6H).
Step-2:
6-Chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
ethyl ester
[0507] 2-(4-Chloro-2-nitro-phenoxy)-malonic acid diethyl ester (4.8
g, 14.5 mmol) was dissolved in EtOH: H.sub.2O (4:5) and then
Na.sub.2S.sub.2O.sub.4. H.sub.2O (17 g, 88.3 mmol) was added. The
reaction mixture was stirred at 60.degree. C. for 5 h. The mixtures
was concentrated under reduced pressure and diluted with water. The
reaction mass was then extracted with ethyl acetate. The organic
layer was washed with water and brine, dried over Na.sub.2SO.sub.4
and concentrated under reduce pressure to afford 3.6 g (97.3%) of
6-Chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
ethyl ester. LC/MS [M+H].sup.+: 256.2. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 11.11 (s, 1H), 7.07 (d, 1H0, 7.01 (dd,
1H), 6.90 (d, 1H), 5.48 (s, 1H), 4.16 (m, 2H), 1.15 (t, 3H)
Step-3:
6-Chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid
[0508] To a solution of
6-Chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
ethyl ester (200 mg, 0.78 mmol) in THF: H.sub.2O (2:1) was added
lithium hydroxide (82 mg, 1.95 mmol). The reaction mixture was
stirred for 5-6 h then concentrated. The crude mass was neutralized
with 50% aqueous acetic acid and extracted with ethyl acetate.
Concentration of the ethyl acetate layer afforded 150 mg (84.2%) of
6-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid.
LC/MS [M+H].sup.+: 227.9. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 13.69 (br s, 1H), 11.01 (s, 1H), 7.04 (d, 1H), 6.98
(d, 1H), 6.88 (br s, 1H), 5.30 (s, 1H).
Step-4:
6-Chloro-2-[(R)-4-(4-fluoro-benzyl)-2-methyl-piperazine-1-carbony-
l]-4H-benzo[1,4]oxazin-3-one
[0509] To a solution of
6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid (100
mg, 0.44 mmol) in DMF was added
(R)-1-(4-fluoro-benzyl)-3-methyl-piperazine (92 mg, 0.44 mmol),
EDCI (109 mg, 0.57 mmol), HOBt (29 mg, 0.22 mmol) and DIPEA (0.2
ml, 1.3 mmol) at 5-10.degree. C. The reaction mixture was stirred
at room temperature for 14-16 hours then diluted with water and
extracted with ethyl acetate. The ethyl acetate layer was
concentrated in vacuo and subjected to column chromatography (45%
ethyl acetate-hexane) to afford 50 (27.2%) of
6-chloro-2-[(R)-4-(4-fluoro-benzyl)-2-methyl-piperazine-1-carbonyl]-4H-be-
nzo[1,4]oxazin-3-one. LC/MS [M+H].sup.+: 417.9. .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. (ppm): 7.88 (m, 1H), 7.27 (m, 2H), 7.00
(m, 2H), 6.93 (m, 2H), 6.78 (m, 1H), 5.45 (m, 1H), 5.39 (m, 1H),
4.56-2.0 (m, 7H), 1.43 (m, 1H), 1.18 (m, 3H). HPLC purity:
95.1%
Example 15
1-{6-Chloro-2-[4-(4-fluoro-benzyl)-piperazine-1-carbonyl]-2,3-dihydro-benz-
o[1,4]oxazin-4-yl}-ethanone
##STR00032##
[0511]
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-benzyl-
)-piperazin-1-yl]-methanone (75 mg, 0.19 mmol) was dissolved in
dichloromethane. Acetyl chloride (0.02 ml, 0.23 mmol) followed
triethylamine (0.05 ml, 0.38 mmol) were then added at 0.degree. C.
The reaction mixture was stirred at room temperature overnight. The
mixture was diluted with water and extracted with ethyl acetate.
The organic layer was dried over sodium sulfate and concentrated.
Purification of crude reaction mass over silica-gel afforded 35 mg
(42.7%) of
1-{6-chloro-2-[4-(4-fluoro-benzyl)-piperazine-1-carbonyl]-2,3-dihydro-ben-
zo[1,4]oxazin-4-yl}-ethanone. LC/MS [M+H].sup.+: 432.2. .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.6 (m, 1H), 7.35 (br s,
2H), 7.12 (m, 3H), 6.95 (d, 1H), 5.39 (br s, 1H0, 4.35 (m, 2H),
3.49 (m, 4H), 2.90 (br s, 1H), 2.32 (s, 3H), 1.50 (m, 1H), 1.23 (m,
3H). HPLC purity: 98.3%
Example 16
(6-Chloro-4-methanesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fl-
uoro-benzyl)-piperazin-1-methanone
##STR00033##
[0513]
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-benzyl-
)-piperazin-1-yl]-methanone (70 mg, 0.18 mmol) was dissolved in
dichloromethane. Methane sulfonyl chloride (0.02 ml, 0.22 mmol)
followed triethylamine (0.05 ml, 0.36 mmol) were then added at
0.degree. C. The reaction mixture was stirred at room temperature
overnight. The mixture was diluted with water and extracted with
ethyl acetate. The organic layer was dried over sodium sulfate and
concentrated. Purification of crude reaction mass over silica-gel
afforded 50 mg (59.4%) of
(6-chloro-4-methanesulfonyl-3,4-dihydro-2H-1-benzo[1,4]oxazin-2-yl)-[4-(4-
-fluoro-benzyl)-piperazin-1-yl]-methanone. LC/MS [M+H].sup.+:
468.1. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.50-7.02
(m, 7H), 5.21 (br s, 1H), 4.40 (m, 4H), 4.05 (m, 2H), 3.69 (m, 1H),
3.01 (br s, 2H), 2.32 (m, 3H), 1.23 (s, 2H), 0.85 (m, 1H). HPLC
purity: 98.8%
Example 17
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[7-(4-fluoro-benzyl)-[1,4]-
oxazepan-4yl]methanone
##STR00034##
[0514] Preparation of 7-(4-fluoro-benzyl)[1,4]oxazepane
##STR00035## ##STR00036##
Step-1:
(3-Hydroxy-propyl)-[(E)-((Z)-2-propenyl)-penta-2,4-dienyl]-carbam-
ic acid tert-butyl ester
[0515] To a solution of 3-benzylamino-propan-1-ol (10 g, 0.06 mol)
in DCM was added 1(N) NaOH and Boc-anhydride (13.5 ml, 0.06 mol) at
0.degree. C. The solution was stirred overnight at room
temperature. The organic layer was separated, washed with water and
concentrated under reduced pressure. The crude product was
subjected to column chromatography (Si-gel, 15% EtOAc-hexane) to
afford 15.1 g of
(3-Hydroxy-propyl)-[(E)-((Z)-2-propenyl)-penta-2,4-dienyl]-carbamic
acid tert-butyl ester in 99% yield. LC/MS [M+H].sup.+: 266.4.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 7.33-7.21 (m,
5-ArH), 4.37 (s, 2H), 3.71 (s, 1H), 3.55 (br s, 3H), 3.37 (br. s,
3H), 1.45 (s, 9H).
Step-2:
(3-propanyl)-[(E)-((Z)-2-propenyl)-penta-2,4-dienyl]-carbamic acid
tert-butyl ester
[0516] To a solution of DMSO (13.5 ml, 0.19 mol) in anhydrous
dichloromethane was added drop wise a solution of oxalyl chloride
(7.2 ml, 0.08 mol) in anhydrous dichloromethane under a nitrogen
atmosphere at -78.degree. C. The resulting mixture was stirred for
15 minutes. A solution of
(3-hydroxypropyl)-[(E)-((Z)-2-propenyl)-penta-2,4-dienyl]-carbamic
acid tert-butyl ester (20.2 g, 0.07 mol) in dichloromethane (85 ml)
was then added dropwise to the reaction mixture over a period of 10
min and stirring was continued for 2 h. To the solution was added
triethyl amine (53 ml, 0.38 mol) and stirring was continued for 5
min at -78.degree. C. followed by stirring at RT 30 min. The
reaction mixture was diluted with water and extracted with
dichloromethane. The combined organic layer was washed with brine,
water, 5% sodium bicarbonate and dried over anhydrous sodium
sulphate. Concentration under reduced pressure afforded 18.1 g of
(3-propanyl)-[(E)-((Z)-2-propenyl)-penta-2,4-dienyl]-carbamic acid
tert-butyl ester in 92% yield. This was used in the next step
without further purification. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 9.63 (s, 1H), 7.37-7.22 (m, 5H), 4.37 (s, 2H), 3.41
(br. s, 2H), 2.60 (t, J=1.0 Hz, 2H), 1.38 (s, 9H).
Step-3: Benzyl-[(E)-4-(4-fluoro-phenyl)-but-3-enyl]-carbamic acid
tert-butyl ester
[0517] To a solution of (4-fluorobenzyl)triphenylphosphonium
bromide (28 g, 0.075 mol) in THF was added t-BuOK (8.5 g, 0.075
mol) portion wise at 0.degree. C. and stirred for 1 h at room
temperature. A solution of
(3-propanyl)-[(E)-((Z)-2-propenyl)-penta-2,4-dienyl]-carbamic acid
tert-butyl ester (18 g, 0.68 mol) in THF was added drop wise to the
generated ylide solution at 0.degree. C. The reaction mixture was
stirred for 5 h at room temperature then extracted with ethyl
acetate. Concentration of the ethyl acetate solution and
purification of the crude product by column chromatography (Si-gel,
3% ethyl acetate-hexane) afforded 10 g (62%) of
benzyl-[(E)-4-(4-fluoro-phenyl)-but-3-enyl]-carbamic acid
tert-butyl ester. LC/MS [M+H].sup.+: 356.2. .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 7.33-6.93 (m, 9 ArH), 6.45 (d, J=11.6
Hz, 1H), 6.02 (br s, 1H), 4.43 (br s, 2H) 3.29 (br, 2H), 2.42 (br,
2H), 1.44 (s, 9H).
Step-4: Benzyl-[(E)-4-(4-fluoro-phenyl)-but-3-enyl]-amine
[0518] To a solution of
benzyl-[(E)-4-(4-fluoro-phenyl)-but-3-enyl]-carbamic acid
tert-butyl ester (10 g, 0.028 mol) in DCM was added trifluoroacetic
acid (21.5 ml, 0.28 mol)) and stirred the solution for about 2 h.
The solution was concentrated and washed with dry ether. The
resulting TFA salt was diluted with a minimum volume of water and
neutralized with aq. NaOH solution at 5-10.degree. C. Extraction of
the aqueous solution with ethyl acetate followed by concentration
of the organic layer afforded 6.8 g (95%) of
benzyl-[(E)-4-(4-fluoro-phenyl)-but-3-enyl]-amine. LC/MS
[M+H].sup.+: 256. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 8.95 (s, 1H), 7.52-7.14 (m, 8 ArH), 6.53 (t, J=16.2 Hz, 1H),
6.21 (m, 1H), 4.18 (d, J=13.4 Hz, 2H), 3.05 (m, 2H), 2.65 (m, 1H),
2.54 (m, 1H).
Step-5: 4-Benzylamino-1-(4-fluoro-phenyl)-butan-2-ol
[0519] Benzyl-[(E)-4-(4-fluoro-phenyl)-but-3-enyl]-amine (14g,
0.027 mol) was dissolved in 100 ml THF and cooled to 0.degree. C.
BH.sub.3-THF (1.5 M, 18.2 ml) was slowly added dropwise and the
solution was stirred for 45 minutes. After warming the reaction
mixture to room temperature, the reaction mixture was concentrated
under reduced pressure.
[0520] Iodine (2 g, 0.013 mol) dissolved in dichloromethane was
added dropwise to a solution of crude amine-borane complex (14 g,
0.26 mol) at room temperature. After 30 minutes, the solvent was
evaporated leaving the crude hydroborated product. Oxidation was
carried out by adding MeOH (200 ml) followed by 20% NaOH (70 ml)
and 30% H.sub.2O.sub.2 (63 ml). The white suspension was stirred
overnight at room temperature. The methanolic reaction mixture was
concentrated and extracted with dichloromethane. The combined
organic layer was dried over sodium sulfate and the solvent was
removed under reduced pressure. The crude reaction mass was
purified through Si-gel (3% meOH-DCM) to afford 4 g (54.2%) of
4-benzylamino-1-(4-fluoro-phenyl)-butan-2-ol. LC/MS [M+H].sup.+:
274.2
Step-6:
N-Benzyl-2-chloro-N-[4-(4fluoro-phenyl)-3-hydroxy-butyl]-acetamid-
e
[0521] To a solution of
4-benzylamino-1-(4-fluoro-phenyl)-butan-2-ol (2 g, 7.3 mmol) in
dichloromethane was added triethylamine (1.1 ml, 8.03 mmol).
Chloroacetyl chloride (0.58 ml, 7.3 mmol) was then added at
0.degree. C. and the mixture stirred for 2 hours at room
temperature. The mixture was then concentrated, diluted with water
and extracted with ethyl acetate. The organic layer was
concentrated to afford 2.78 g
N-benzyl-2-chloro-N-[4-(4-fluoro-phenyl)-3-hydroxy-butyl]-acetamide.
LC/MS [M+H].sup.+: 350. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm):7.38-7.04 (m, 9H), 4.74 (d, J=6.1 Hz, 1H), 4.62-4.35 (m, 5H),
3.57 (br s. 1H), 3.27 (m, 1H), 2.59 (d, J=6.1 Hz, 2H), 1.72 (m,
1H).
Step-7: 4-Benzyl-7-(4-fluoro-benzyl)-[1,4]oxazepan-3-one
[0522] To a solution of
N-Benzyl-2-chloro-N-[4-(4-fluoro-phenyl)-3-hydroxy-butyl]-acetamide
(2.9 g, 8.3 mmol) in THF was added sodium hydride (0.26 g, 10.7
mmol) portion wise at 0.degree. C. The resulting mixture was
stirred at room temperature. Excess NaH was quenched with saturated
aqueous solution of ammonium chloride at 0.degree. C. and with
ethyl acetate. The organic layer was concentrated to afford 2.65 g
of 4-benzyl-7-(4-fluoro-benzyl)-[1,4]oxazepan-3-one. LC/MS
[M+H].sup.+: 314. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm):
7.34-6.99 (m, 9H), 4.90-4.26 (m, 5H), 3.39 (d, J=13.5 Hz, 1H), 2.06
(m, 1H), 1.74 (m, 1H).
Step-8: 4-Benzyl-7-(4-fluoro-benzyl)[1,4]oxazepane
[0523] To a solution of
4-benzyl-7-(4-fluoro-benzyl)-[1,4]oxazepan-3-one (2.65g, 8.55 mmol)
in THF was added LiAlH.sub.4 (0.65 g, 17.1 mmol) at 0.degree. C.
The resulting mixture was heated to reflux for 2 houra. Excess
LiALH.sub.4 was quenched with saturated aqueous sodium sulfate
solution and with ethyl acetate. The organic layer was concentrated
and purified through Si-gel (10% ethyl acetate-hexane) to afford
1.3 g (50.3%) of 4-benzyl-7-(4-fluoro-benzyl)-[1,4]oxazepane. LC/MS
[M+H].sup.+: 300.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.32-7.05 (m, 9H), 3.88-3.70 (m, 2H), 3.57 (s, 2H), 3.44 (m,
1H), 2.722.52 (m, 5H), 1.81 (m, 1H), 1.68 (m, 1H)
Step-9: 7-(4-Fluoro-benzyl)-[1,4]oxazepane
[0524] 4-benzyl-7-(4-fluoro-benzyl)-[1,4]oxazepane (1.3 g, 4.3
mmol) dissolved in ethanol was hydrogenated with 10% Pd-C (140 mg)
for 12 hour. The catalyst was removed by filtration through a
celite bed. Concentration of the ethanol solution afforded 850 mg
(93%) of 7-(4-fluoro-benzyl)-[1,4]oxazepane. LC/MS [M+H].sup.+:
210.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.16-6.92
(m, 4 ArH), 3.84 (m, 2H), 3.48 (m, 1H), 2.92 (m, 3H), 2.87 (m, 1H),
2.65 (m, 1H), 1.89 (m, 1 h, 1.62 (m, 1H).
[0525]
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[7-(4-fluoro-benzyl-
)-[1,4]oxazepan-4-yl]-methanone was prepared by coupling
7-(4-Fluoro-benzyl)-[1,4]oxazepane with
6-Chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic acid
4-tert-butyl ester followed by deboc with TFA using the procedure
described in Example 8. LC/MS [M+H].sup.+: 405.4. .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. (ppm): 7.16-6.34 (m, 7H), 4.74 (m, 1H),
4.72-3.23 (m, 10H), 2.80-2.66 (m, 2H), 1.72 (m, 2H). HPLC purity:
99.6%
Example 18
1-{6-Chloro-2-[4-(4-fluoro-benzyl)-piperazine-1-carbonyl]-2,3-dihydro-benz-
o[1,4]oxazin-4-yl}-2-dimethylamino-ethanone
##STR00037##
[0527]
(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-benzyl-
)-piperazin-1-yl]-methanone (200 mg, 0.51 mmol) was dissolved in
dichloromethane. Chloroacetyl chloride (0.04 ml, 0.51 mmol)
followed by triethylamine (0.08 ml, 0.56 mmol) were then added at
0.degree. C. The reaction mixture was stirred at room temperature
overnight. The mixture was diluted with water and extracted with
ethyl acetate. The organic layer was dried over sodium sulfate and
concentrated to afford 240 mg of crude product. 120 mg of the crude
product in Me.sub.2NH-THF was heated at 70.degree. C. in a sealed
tube overnight. The reaction mixture was concentrated to afford 85
mg (68.8%) of
1-{6-chloro-2-[4-(4-fluoro-benzyl)-piperazine-1-carbonyl]-2,3-dihydro-ben-
zo[1,4]oxazin-4-yl}-2-dimethylamino-ethanone. LC/MS [M+H].sup.+:
475.1. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 8.44-6.86
(m, 7H), 5.36 (br s, 1H), 4.01 (br s, 1H), 3.62 (br s, 1H), 3.49
(m, 4H), 2.96 (d, 1H), 2.82 (d, 1H), 2.58 (m, 3H), 2.36 (m, 2H),
2.24 (s, 6H), 1.35 (m, 1H), 1.16 (m, 1H). HPLC purity: 95.1%
Example 19
(6-Chloro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-benz-
yl)-piperazin-1-yl]-methanone
##STR00038##
[0529]
(6-chloro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluo-
ro-benzyl)-piperazin-1-yl]-methanone was prepared using a process
similar to that described in Example 12. LC/MS [M+H].sup.+: 404.0.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 8.00-6.55 (m, 7H),
4.82 (m, 1H), 3.72 (m, 2H), 3.57-3.36 (m, 6H), 2.89 (s, 3H),
2.48-2.40 (m, 4H). HPLC purity: 90.1%
Example 20
1-{6-Chloro-2-[4-(4-fluoro-benzyl)-piperazine-1-carbonyl]-2,3-dihydro-benz-
o[1,4]oxazin-4-yl}-2-methylamino-ethanone
##STR00039##
[0531]
1-{6-Chloro-2-[4-(4-fluoro-benzyl)-piperazine-1-carbonyl]-2,3-dihyd-
ro-benzo[1,4]oxazin-4-yl}-2-methylamino-ethanone was prepared
through aminolysis of the ester with a THF solution methylamine by
a process similar to that described above in Example 18. LC/MS
[M+H].sup.+: 461.2.
[0532] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 8.34-7.00
(m, 7H), 5.39 (br s, 1H), 4.27 (m, 2H), 3.79-3.31 (m, 7H), 2.66 (m,
1H), 2.53-0.85 (7H). HPLC purity: 91.1%
Example 21
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-benzoyl)-pipe-
ridin-1-yl]-methanone
##STR00040##
[0534]
(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-benzoy-
l)-piperidin-1-yl]-methanone was prepared from 4-fluorobenzoyl
piperidine (Alfa Aesar, USA) by the amide coupling method described
above in Example 8. LC/MS [M+H].sup.+: 403.0. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 8.10 (br s, 2H), 7.37 (t, 2H), 6.68
(br s, 1H), 6.58s, 1H), 6.44 (d, 1H), 4.91 (br s, 1H), 4.35 (t,
1H), 4.03 (d, 1H), 3.75 (m, 1H), 3.48 (m, 2H), 3.31 (m, 2H), 2.85
(m, 2H), 1.99 (d, 2H), 1. 58 (m, 2H). HPLC purity: 92.2%
Example 22
6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
[1-(4-fluoro-benzyl)-piperidin-4-yl]-amide
##STR00041##
[0535] Preparation of 1-(4-fluoro-benzyl)-piperidin-4-ylamine
##STR00042##
Step-1: [1-(4-fluoro-benzyl)-piperidin-4-yl]carbamic acid
tert-butyl ester
[0536] To a solution of piperidin-4-yl-carbamic acid tert-butyl
ester (1 g, 4.99 mmol) in THF was added triethylamine (1.4 ml, 9.98
mmol) and 4-fluorobenzyl bromide (0.81 ml, 6.49 mmol) at 0.degree.
C. The reaction mixture was stirred at room temperature for 3 hour.
The mixture was then concentrated, diluted with water and extracted
with ethyl acetate. The organic layer was washed with water and
dried over sodium sulfate. The organic layer was concentrated to
afford 1.4 g (91%) of [1-(4-fluoro-benzyl)-piperidin-4-yl]-carbamic
acid tert-butyl ester. LC/MS [M+H].sup.+: 309.3
Step-2: 1-(4-Fluoro-benzyl)-piperidin-4-ylamine
[0537] To a solution of
1-(4-fluoro-benzyl)-piperidin-4-yl]-carbamic acid tert-butyl ester
(1.35 g, 4.3 mmol)) in DCM was added trifluoroacetic acid (0.3 ml,
3.9 mmol). The reaction mixture was stirred for about 5 h then
concentrated and washed with dry ether. The resulting TFA salt was
diluted with a minimum volume of water and neutralized with aq.
NaOH solution at 5-10.degree. C. Extraction of the neutralized
solution with ethyl acetate followed by concentration afforded 900
mg (100%) of 1-(4-fluoro-benzyl)-piperidin-4-ylamine.LC/MS
[M+H].sup.+:209.2
[0538] 6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
[1-(4-fluoro-benzyl)-piperidin-4-yl]-amide was prepared from
6-chloro-2,3-dihydro-benzo[1,4]oxazine -4-carboxylic acid
tert-butyl ester-2-carboxylic acid using a process similar to that
described in Example 8. LC/MS [M+H].sup.+: 404.1. .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. (ppm): 7.80-6.17 (8-ArH), 4.44 (m, 1H),
3.50 (m, 1H), 3.44 (m, 1H), 3.40 (m, 1H), 3.37 (m, 2H), 3.28 (m,
1H), 2.67 (m, 1H), 1.98 (m, 2H), 1.66 (m, 2H), 1.51 (m, 2H), 1.23
(m, 1H). HPLC purity: 93.4%
Example 23
1-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fluoro-benzy-
l)-piperidine-4-carbonitrile
##STR00043##
[0539] Preparation of
4-(4-Fluoro-benzyl)-piperidine-4-carbonitrile:
##STR00044##
Step-1: 4-Cyano-4-(4-fluoro-benzyl)-piperidine-1-carboxylic acid
tent butyl ester
[0540] 1.6 (M) solution n-butyl lithium in hexane (15.8 ml, 26.6
mmol) was added to an ice-chilled solution of diisopropylamine (3.2
ml, 22.8 mmol) in THF. The resulting mixture was stirred at room
temperature for 1 hour. The solution was then cooled to -78.degree.
C. and a solution of 4-cyano-1-boc piperidine (4.0 g, 19 mmol) in
THF was added dropwise. The mixture was warmed to -40.degree. C.
over a period of 1 hour, then cooled to -78.degree. C. A solution
of 4-fluorobenzyl bromide in THF was added dropwise and the
resuling mixture was stirred at -78.degree. C. for 4 hours then
quenched at 0.degree. C. by the addition of saturated aqueous
solution of ammonium chloride. The product was extracted with ethyl
acetate. The organic layer was washed with brine solution and dried
over sodium sulfate. The organic layer was concentrated and the
crude mass was crystallized from hexane to afford 3 g (49.6%) of
4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carboxylic acid tert butyl
ester. LC/MS [M+H].sup.+: 319.4
Step-2: 4-(4-Fluoro-benzyl)-piperidine-4-carbonitrile
[0541] Trifluoroacetic acid (5.7 ml, 75.2 mmol) was added to a
solution of 4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carboxylic
acid tert butyl ester (3 g, 9.4 mmol) in DCM and the resuoing
mixture was stirred for about 5 h. The reaction mass was
concentrated and washed with dry ether. The TFA salt was diluted
with a minimum volume of water and neutralized with aq. NaOH
solution at 5-10.degree. C. Extraction of the neutralized solution
with ethyl acetate followed by concentration of the organics
afforded 2.1 mg (97.6%) of
4-(4-Fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
219.4
[0542]
1-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fluor-
o-benzyl)-piperidine-4-carbonitrile was prepared from
6-Chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic acid
4-tert-butyl ester using a process similar to that described in
Example 8. LC/MS [M+H].sup.+: 414.3. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 7.34 (d, 2H), 7.19 (t, 2H), 6.68 (m,
1H), 6.58 (s, 1H), 6.47 (d, 1H), 6.18 (s, 1H), 4.92 (br s, 1H0,
4.39 (m, 1H), 4.09 (t, 1H), 3.37 (m, 1H), 3.28 (m, 1H), 3.20 (m,
1H), 2.95 (m, 2H), 2.69 (m, 1H), 1.81 (m, 3H), 1.56 (m, 1H), HPLC
purity: 99.7%
Example 24
[1-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)-4-(4-fluoro-benzy-
l)-piperidin-4-yl]-methylamine
##STR00045##
[0544]
[4-Cyano-4-(4-fluoro-benzyl)-piperidin-1-yl]-(6-chloro-3,4-dihydro--
2H-benzo[1,4]oxazin-2-yl)-methanone 100 mg (0.24mmol) in THF was
refluxed with BH.sub.3-DMS (0.27 ml, 2.4 mmol) for 20 hours. The
reaction mixture was refluxed with 5 ml methanol for one hour then
concentrated. Purification of the residue using column
chromatography over si-gel afforded 23 mg (24%) of
[4-aminomethyl-4-(4-fluoro-benzyl)-piperidin-1-yl]-(6-chloro-3,4-dihydro--
2H-benzo[1,4]oxazin-2-yl)-methanone. LC/MS [M+H].sup.+: 404.4.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.19 (t, 2H),
7.10 (t, 2H), 6.62 (d, 1H), 6.55 (d, 1H), 6.41 (dd, 1H), 6.06 (s,
1H), 5.11 (br s, 2H), 4.08 (m, 1H), 2.96 (m, 1H), 2.66 (s, 2H),
2.50 (m, 1H), 2.45 (m, 2H), 2.32 (m, 4H), 1.34 (m, 6H). HPLC
purity: 97.9%
Example 25
2-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-1-[(R)-4-(4-fluoro-benzy-
l)-2-methyl-piperazin-1-yl]-ethanone
##STR00046##
[0545] Step-1: (Z)-4-(5-Chloro-2-hydroxy-phenylamino)-but-2-enoic
acid methyl ester
[0546] NaHCO.sub.3 (1.4 g, 16.7 mmol) and methyl-4-bromocrotonate
(1.64 ml, 13.9 mmol) were added to 4-chloro-2-nitrophenol (2 g,
13.9 mmol) in methanol and the resulting mixture was stirred
overnight at room temperature. The mixture was then concentrated,
diluted with water and extracted with ethyl acetate. The organic
layer was dried over sodium sulfate and concentrated under reduced
pressure. The crude mass was purified using column chromatography
over Si-gel (70% DCM-hexane) to afford 2 g (60%) of
(Z)-4-(5-chloro-2-hydroxy-phenylamino)-but-2-enoic acid methyl
ester. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 7.04-6.99
(dt, 1H), 6.64-6.47 (4H), 6.02 (br d, J=16 Hz, 1H), 5.1 (mbr s,
1H), 3.95 (t, 2H), 3.74 (s, 3H)
Step-2: (6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-acetic acid
methyl ester
[0547] A catalytic amount of K.sub.2CO.sub.3 (136 mg, 0.9 mmol) was
added to (Z)-4-(5-Chloro-2-hydroxy-phenylamino)-but-2-enoic acid
methyl ester (2 g, 8.3 mmol) in methanol and the mixture was
stirred at room temperature for 2 hours. The solution was then
concentrated, diluted with water and extracted with ethyl acetate.
The organic layer was dried over sodium sulfate and concentrated
under reduced pressure to afford 1.5 g (75%) of
(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-acetic acid methyl
ester. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 6.72-6.56
(m, 3H), 4.53 (m, 1H), 3.81 (s, 1H), 3.72 (s, 3H), 3.46 (d, 1H),
3.17 (m, 1H), 2.79-2.58 (m, 2H).
Step-3:
6-Chloro-2-methoxycarbonylmethyl-2,3-dihydro-benzo[1,4]oxazine-4--
carboxylic acid tert-butyl ester
[0548] DMAP (1.2 g, 9.93 mmol) and (Boc).sub.2O (2.75 ml, 13.2
mmol) were added to
(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-acetic acid methyl
ester (1.6 g, 6.62mmol) in THF and the resulting mixture was
stirred overnight under reflux. The mixture was then concentrated,
diluted with water and extracted with ethyl acetate. The organic
layer was dried over sodium sulfate and concentrated under reduced
pressure. The crude mass was purified using column chromatography
over Si-gel (5%-ethyl acetate-hexane) to afford 1.7 g (75%) of
6-chloro-2
methoxycarbonylmethyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester. LC/MS [M+H].sup.+: 342. .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. (ppm):7.8 (s, 1H), 6.93-6.76 (m, 2H), 4.59
(m, 1H), 4.1-4.07 (dd, 1H), 3.74 (s, 3H), 3.46 (m, 1H), 2.74-2.61
(m, 2H) 1.56 (s, 9H).
Step-4:
2-Carboxymethyl-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxyl-
ic acid tert-butyl ester
[0549] To a solution of
6-chloro-2-methoxycarbonylmethyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxyl-
ic acid tert-butyl ester (1.7 g, 4.9 mmol) in THF: H.sub.2O (2:1)
was added lithium hydroxide (418 mg, 9.95 mmol). The reaction
mixture was stirred for 5-6 h then concentrated. The crude product
was neutralized with 50% aqueous acetic acid and extracted with
ethyl acetate. Concentration of the ethyl acetate layer afforded
1.35 g (83%) of
2-carboxymethyl-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
(ppm):7.8 (s, 1H), 7.06-6.77 (m, 3H), 4.6 (m, 1H), 4.13 (d, 1H),
3.48 (m, 1H), 2.79-2.63 (m, 2H), 1.53 (s, 9H).
Step-5:
6-Chloro-2-{2-[(R)-4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-
-oxo-ethyl}-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tent-butyl ester
[0550] (R)-1-(4-fluoro-benzyl)-3-methyl-piperazine (65 mg, 0.31
mmol), EDCI (89 mg, 0.47 mmol), HOBt (50 mg, 0.37 mmol) and DIPEA
(0.16 ml, 0.93 mmol) were added to
2-carboxymethyl-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester (100 mg, 0.31 mmol) in DMF at 5-10.degree. C.
The resulting mixture was stirred at room temperature for 14-16
hours then diluted with water and extracted with ethyl acetate. The
ethyl acetate layer was concentrated in vacuo and subjected to
column chromatography (12% ethyl acetate-hexane) to afford 98 mg
(61%) of
6-chloro-2-{2-[(R)-4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-eth-
yl}-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester. LC/MS [M+H]: 518.1
Step-6:
2-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-1-[(R)-4-(4-flu-
oro-benzyl)-2methyl-piperazin-1-yl]-ethanone
[0551] Trifluoroacetic acid (0.1 ml, 1.4 mmol) ws added to a
solution of
6-chloro-2-{2-[(R)-4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-eth-
yl}-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester (90 mg, 0.17 mmol) in DCM and the resuling mixture was
stirred for about 5 h. The reaction mass was then concentrated and
washed with dry ether. The TFA salt was diluted with a minimum
volume of water and neutralized with aq. NaOH solution at
5-10.degree. C. Extraction of the neutralized solution followed by
concentration afforded 30 mg (42%) of
2-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-1-[(R)-4-(4-fluoro-benz-
yl)-2-methyl-piperazin-1-yl]-ethanone. LC/MS [M+H].sup.+: 418.3.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.29-6.6 (m,
7H), 4.74 (br s, 1H), 4.59 (br s, 1H), 4.38 (t, 1H), 4.00 (br s,
1H), 3.81 (brs, 1H), 3.55-2.60 (m, 8H), 2.16-1.96 (m, 2H), 1.26 (br
s, 3H). HPLC purity: 95.1%
Example 26
2-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-1-1-[7-(4-fluoro-benzyl)-
-[1,4]oxazepan-4-yl]-ethanone
##STR00047##
[0553] 7-(4-Fluoro-benzyl)-[1,4]oxazepane was prepared as described
in Example 17.
[0554]
2-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-1-[7-(4-fluoro-be-
nzyl)-[1,4]oxazepan-4-yl]-ethanone was prepared by a process
similar to that described in Example 25. LC/MS 8 M+H].sup.+: 419.2.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.25-6.39 (m,
7H), 6.1 (s, 1H), 4.36 (br s, 1H), 3.86-3.39 (m, 5H), 3.00 (m, 2H),
2.77-2.55 (m, 5H), 1.84 (m, 2H), 1.51 (m, 2H). HPLC purity:
90.7%
Example 27
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile
##STR00048##
[0556] 4-(4-Fluoro-benzyl)-piperidine-4-carbonitrile was prepared
as described above in Example 23.
Step 1: 2-chloro-5-fluoro-4-nitroanisole
[0557] Potassium nitrate (3.15 g, 0.031 mol) was added portion wise
at 0.degree. C. to 2-Chloro-5-fluoroanisole (5 g, 0.031 mol)
dissolved in conc. H.sub.2SO.sub.4. The reaction mixture was
stirred for 1 h. then poured into ice. The resulting precipitate
was extracted with ethyl acetate and the organic layer was washed
with water, saturated bicarbonate solution and brine. The organics
were then dried over Na.sub.2SO.sub.4 and concentrated under reduce
pressure to afford 5.5 g (86%) of 2-chloro-5-fluoro-4-nitroanisole.
GCMS [m/z]: 205. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm):
8.30 (d, J=7.9 Hz, 1H), 7.48 (d, J=13.4 Hz, 1H), 4.01 (s, 3H).
Step 2: 4-Chloro-5-methoxy-2-nitrophenol
[0558] 2-chloro-5-fluoro-4-nitroanisole (2 g, 9.73 mmol) was
refluxed overnight with 6 (N) NaOH solution. The pH of the solution
was adjusted to 1 with 6(N) HCl. The product was extracted with
ethyl acetate, which was washed with water, saturated bicarbonate
solution and brine. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated under reduce pressure to afford
1.5 g (75.5%) of 4-chloro-5-methoxy-2-nitrophenol. GCMS [m/z]:
203.5. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 10.9 (s,
1H), 8.14 (s, 1H), 6.59 (s, 1H), 3.97 (s, 3H).
Step 3: Diethyl 4-chloro-5-methoxy-2-nitro-phenyloxymalonate
[0559] 4-Chloro-5-methoxy-2-nitrophenol (6.3 g, 0.031 mol) was
dissolved in a minimum volume of DMF. Anhydrous K.sub.2CO.sub.3
(8.54 g, 0.062 mol) and diethyl-2-bromomalonate (6.8 ml, 0.034 mol)
were added to the solution and the resulting mixture was stirred at
room temperature overnight. The reaction mixture was diluted with
ice-water and extracted with ethyl acetate. The organic layer was
washed successively with water and brine and then dried over
Na.sub.2SO.sub.4. The organic layer was concentrated under reduced
pressure and purification of the residue by flash chromatography
(silica-gel, 2% EtOAc-hexane) afforded 4.39 g (40%) of diethyl
4-chloro-5-methoxy-2-nitro-phenyloxymalonate.LC/MS [M+H].sup.+:
362.1. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 8.11 (s,
1H), 6.83 (s, 1H), 5.19 (s, 1H), 4.33 (m, 4H), 3.94 (s, 3H), 1.32
(m, 6H)
Step 4:
Ethyl-6-Chloro-7-methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-2-
-carboxylate
[0560] 4-chloro-5-methoxy-2-nitro-phenyloxymalonate (725 mg, 2
mmol) was dissolved in EtOH: H.sub.2O (4:5) and
Na.sub.2S.sub.2O.sub.4.H.sub.2O (2.34 g, 12 mmol) was added. The
reaction mixture was stirred at 60.degree. C. for 5 h. The reaction
mixture was then concentrated under reduced pressure, diluted with
water and extracted with ethyl acetate. The organic layer was
washed with water and brine, dried over Na.sub.2SO.sub.4 and
concentrated under reduce pressure to obtain 200 mg (35%) of
ethyl-6-chloro-7-methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine--
2-carboxylate. LC/MS [M+H].sup.+: 286.2. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 7.84 (br s, 1H), 6.99 (s, 1H), 6.73
(s, 1H), 4.26 (m, 2H), 1.28 (t, J=6.8 Hz, 3H).
Step 5:
Ethyl-6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbo-
xylate
[0561] BH.sub.3-DMS (0.17 ml, 2.17 mmol) was added at 0.degree. C.
to a solution of
ethyl-6-chloro-7-methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxy-
late (620 mg, 2.17 mmol) in THF and the resulting mixture was
stirred overnight at room temperature. The mixture was then cooled
to 0.degree. C., quenched with MeOH and the solution was refluxed
for 1 h. The reaction mixture was concentrated under reduced
pressure. Purification of the residue by flash chromatography
(silica-gel, 8% EtOAc-hexane) afforded 150 mg (25%) of
ethyl-6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylate.
LC/MS [M+H].sup.+: 272.3. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 6.63 (s, 2H), 5.61 s, 1H), 4.95 (br s, 1H), 4.13 (q,
J=7 Hz, 2H), 3.71 (s, 3H), 1.8 (t, J=7 Hz, 3H)
Step 6:
6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid
[0562] Lithium hydroxide (71 mg, 1.69 mmol) was added to a solution
of
ethyl-6-chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylate
(230 mg, 0.84 mmol) in THF: H.sub.2O (2:1) and the resulting
solution was stirred for 5-6 h then concentrated. The crude product
was neutralized with 50% aqueous acetic acid and extracted with
ethyl acetate. Concentration of the ethyl acetate layer afforded
170 mg (83%) of
6-chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid. LC/MS [M+H].sup.+: 244.3. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 6.54 (s, 1H), 6.50 (s, 1H), 5.37 (s, 1H), 4.07(d,
J=4.9, 1H), 3.68 (s, 3H), 3.08 (m, 1H).
Step-6:
(6-Chloro-7-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[{(4-fluor-
ophenyl)methyl}-1-piperidinyl}]-methanone
[0563] To a solution of
6-chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid (130 mg, 0.53 mmol) in DMF was added
4-cyano-4-(4-fluoro-benzyl)-piperidine (126.5 mg, 0.0.58 mmol),
EDCI (152.8 mg, 0.79 mmol), HOBt (86.34 mg, 0.63 mmol) and DIPEA
(0.12 ml, 1.6 mmol) at 5-10.degree. C. and the resulting mixture
was stirred at room temperature for 14-16 hours. The mixture was
then diluted with water and extracted with ethyl acetate. The
organic layer was concentrated under reduced pressure and the
residue was purified by flash chromatography (silica-gel, 2%
MeOH-DCM) to afford 22 mg (7%) of
(6-chloro-7-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[{(4-fluorophenyl)-
methyl}-1-piperidinyl}]-methanone. LC/MS [M+H].sup.+:444.3.
[0564] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.34 (br
s, 2H), 7.18 (m, 2H), 6.64-6.56 (m, 2H), 5.58 (s, 1H), 4.97 (m,
1H), 4.37 (m, 1H) 4.08 (m, 1H), 3.83 (m, 1H) 3.71 (s, 3H), 3.21 (m,
1H), 2.95 (m, 1H),1.87 (m, 3H), 1.54 (m, 1H). HPLC purity:
99.23%.
Example 28
2-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-1-[4-(4-fluoro-benzyl)-[-
1,4]diazepan-1-yl]-ethanone
##STR00049##
[0566]
2-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-benz-
yl)-[1,4]diazepan-1-yl]-ethanone was prepared using a procedure
similar to that described in Example 25. LC/MS [M+H].sup.+: 418.3.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.25-6.56 (m,
7H), 4.64 (m, 1H), 3.81-3.48 (m, 8H), 3.19 (m, 1H), 2.79 (m, 1H),
2.62 (m, 4H), 1.84 (m, 2H). HPLC purity: 95.2%
Example 29
2-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-1-[2-(4-fluoro-benzyl)-(-
1,4]oxazepan-4yl]-ethanone
##STR00050##
[0567] Preparation of 2-(4-fluoro-benzyl)-[1,4]oxazepane
##STR00051##
Step-1: N-Benzyl-2-chloro-N-(3-hydroxy-propyl)-acetamide
[0568] To a solution of 3-benzylamino-propan-1-ol (28 g, 0.17 mol)
solution in DCM was added triethylamine (25.9 ml, 0.19 mol) and
chloroacetyl chloride (13.4 ml, 0.17 mol) at 0.degree. C. The
mixture was stirred for 2 h at room temperature, then concentrated
and extracted with ethyl acetate. Concentration of organic layer
afforded 41 g (93%) of
N-benzyl-2-chloro-N-(3-hydroxy-propyl)-acetamide. LC/MS
[M+H].sup.+: 242.3
Step-2: 4-Benzyl-[1,4]oxazepan-3-one
[0569] A solution of
N-benzyl-2-chloro-N-(3-hydroxy-propyl)-acetamide (30 g, 0.12 mol)
in THF was added to a suspension of sodium hydride (6.25 g, 0.13
mol) in dry THF at 0.degree. C. and the resulting mixture was
stirred overnight. Excess sodium hydride was quenched with
saturated NH.sub.4Cl solution and extracted with ethyl acetate. The
organic layer was washed with water and brine solution. The
combined organic phase was concentrated under reduced pressure and
purified through column chromatography (Si-gel, 1-2% MeOH-DCM) to
afford 16 g of 4-benzyl-[1,4]oxazepan-3-one in 68% yield. LC/MS
[M+H].sup.+:206.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.35-7.24 (m, 5H), 4.51 (s, 2H), 4.19 (s, 2H), 3.73 (t,
J=5.6 Hz, 2H), 3.43 (t, J=4.9 Hz, 2H), 1.69 (m, 2H)
Step-3: 4-Benzyl-2-(4-fluoro-benzyl)-[1,4]oxazepan-3-one
[0570] LDA solution in THF (5.9 mmol) was added to a solution of
4-benzyl-[1,4]oxazepan-3-one (1 g, 4.9 mmol) in THF at -78.degree.
C. The solution was stirred for 1 h at -78.degree. C. then
4-fluorobenzyl bromide (920 mg, 4.9 mmol) was added. The solution
was allowed to warm to room temperature over a period of 4 h. The
reaction mixture was then quenched with saturated NH.sub.4Cl
solution and extracted with ethyl acetate. The organic layer was
washed with water and brine solution. The organic phase was
concentrated in vacuo and purified through column chromatography
(Si-gel, 5-10% ethyl acetate-hexane) to afford 1.1 g (49%) of
4-benzyl-2-(4-fluoro-benzyl)-[1,4]oxazepan-3-one. LC/MS
[M+H].sup.+:314.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.35-7.06 (9 Ar H), 4.59-4.41 (m, 3H), 3.92 (m, 1H), 3.69
(m, 1H), 3.41 (m, 1H), 3.3 (m, 1H), 3.04 (dd, J=14.5, 3.7 Hz, 1H),
2.80 (m, 1H), 1.53 (s, 2H).
Step-4: 4-Benzyl-2-(4-fluoro-benzyl)-[1,4]oxazepane
[0571] Lithium aluminum hydride (726 mg, 19.1 mmol) was added
portion wise at 0.degree. C. o a solution of
4-benzyl-2-(4-fluoro-benzyl)-[1,4]oxazepan-3-one (3.08 g, 9.6 mmol)
in THF. The mixture was refluxed for 2 h and excess LiALH.sub.4 was
quenched with aq. NaOH solution at 0.degree. C. The reaction
mixture was filtered through celite bed. Concentration of the
organic layer afforded 2.5 g (89%) of
4-benzyl-2-(4-fluoro-benzyl)-[1,4]oxazepane. LC/MS
[M+H].sup.+:300.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.29-7.01 (9 Ar H), 3.73 (m, 2H), 3.56 (m, 3H), 2.78-2.31 9
m, 5H), 1.79-1.70 (2H).
Step-5: 2-(4-Fluoro-benzyl)-[1,4]oxazepane
[0572] 4-benzyl-2-(4-fluoro-benzyl)-[1,4]oxazepane (2.5 g) was
hydrogenated using 10% Pd-C in ethanol for 5-10 h. The catalyst was
removed by filtration through a celite bed. Concentration of the
ethanol solution afforded 1.8 g (97%) of
2-(4-fluoro-benzyl)-[1,4]oxazepane. LC/MS [M+H].sup.+:210.3.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.22-7.05 (4 Ar
H), 3.75 (m, 1H), 3.54 (m, 2H), 3.88 (m, 2H), 2.63 (m, 3H), 2.41 9
m, 1H), 1.68 (m, 2H).
[0573]
2-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-1-[2-(4-fluoro-be-
nzyl)-[1,4]oxazepan-4-yl]-ethanone was prepared using a procedure
similar to that described in Example 25. LC/MS [M+H].sup.+: 419.3.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.28-7.06 (m,
7H), 6.09 (s, 1H), 4.36 (m, 1H), 4.02-3.66 (m, 4H), 3.38 (m, 2H),
3.14-2.60 (m, 7H), 1.80 m, 2H). HPLC purity: 95.47%
Example 30
6-Chloro-2-{2-[2-(4-fluoro-benzyl)-[1,4]oxazepan-4-yl]-ethyl}-3,4-dihydro--
2H-benzo[1,4]oxazine
##STR00052##
[0575] A solution of
2-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-1-[2-(4-fluoro-benzyl)--
[1,4]oxazepan-4-yl]-ethanone (100 mg, 0.24 mmol) in THF was
refluxed with BH.sub.3-THF (0.13 ml, 1.19 mmol) for 8 hours. The
reaction mixture was refluxed with 5 ml methanol for an additional
hour, the concentrated. Purification of the residue using column
chromatography over si-gel (1.5% MeOH-DCM) afforded 62 mg (64.5%)
of
6-chloro-2-{2-[2-(4-fluoro-benzyl)-[1,4]oxazepan-4-yl]-ethyl}-3,4-dihydro-
-2H-benzo[1,4]oxazine. LC/MS [M+H].sup.+: 405.4. .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. (ppm): 7.30-6.41 (m, 7H), 6.07 (s, 1H),
3.97 (br s, 1H), 3.97-3.49 (m, 5H), 2.98-2.50 (m, 7H), 2.34 (m,
1H), 1.70 (m, 4H). HPLC purity: 98.1%
Example 31
4-(4-Chloro-benzyl)-1-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbony-
l)-piperidine-4-carbonitrile
##STR00053##
[0576] Preparation of
4-(4-Chloro-benzyl)-piperidine-4-carbonitrile
[0577] 4-(4-chloro-benzyl)-piperidine-4-carbonitrile was prepared
using a procedure similar to that described in Example 23. LC/MS
[M+H].sup.+: 219.2. .sup.1H-NMR (400MHz, DMSO-d.sub.6) .delta.
(ppm): 7.33-7.15 (4 Ar H), 2.90 (t, J=12.8 Hz, 2H), 2.86 (s, 2H),
2.55 (t, J=12.2 Hz, 2H), 1.65 (d, J=12.9 Hz, 2H), 1.46 (t, J=3.4
Hz, 2H). HPLC purity: 99%
[0578] 6-chloro-2,3-dihydro-benzo[1,4]oxazine -4-carboxylic acid
tert-butyl ester-2-carboxylic acid was prepared using a procedure
similar to that described in in Example 8. GCMS [m/z-Boc]: 213.
.sup.1H-NMR (400MHz, DMSO-d.sub.6) .delta. (ppm): 13.40 (br s, 1H),
7.72-6.95 (3 Ar H), 5.06 (br, s, 1H), 4.40 (dd, J=11.2, 2.6 Hz,
1H), 3.55 (dd, J=10.8, 3.0 Hz, 1H), 1.38 (s, 9H)
Step 1:
6-Chloro-2-[4-(4-chloro-benzyl)-4-cyano-piperidine-1-carbonyl]-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tent-butyl ester
[0579] To a solution of
6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester-2-carboxylic acid (200 mg, 0.64 mmol) in DMF was added
4-cyano-4-(4-chloro-benzyl)-piperidine (140 mg, 0.64 mmol), EDCI
(160 mg, 0.83 mmol), HOBt (43 mg, 0.32 mmol) and DIPEA (0.32 ml,
1.42 mmol) at 5-10.degree. C. and the resulting mixture was stirred
at room temperature for 14-16 hours. The mixture was then diluted
with water and extracted with ethyl acetate. The organic layer was
concentrated under reduced pressure and the residue was purified by
flash chromatography (silica-gel, 2% MeOH-DCM) to afford 230 mg
(70%) of
6-Chloro-2-[4-(4-chloro-benzyl)-4-cyano-piperidine-1-carbonyl]-2,3-dihydr-
o-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester. LC/MS
[M+H].sup.+: 514.2. .sup.1N-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.67-6.92 (7 Ar H), 5.44 (s, 1H), 5.37 (s, 1H), 4.33 (d,
J=12.9 Hz, 1H), 4.10 (m, 2H), 3.82 (m, 3H), 2.95 (s, 2H), 1.78 (m,
2H), 1.45 (s, 9H), 1.23 (s, 1H).
Step-2:
4-(4-Chloro-benzyl)-1-(6-chloro-3,4dihydro-2H-benzo[1,4]oxazine-2-
-carbonyl)-piperidine-4-carbonitrile
[0580] Trifluoroacetic acid (1.72 ml, 22.3 mmol) was added to a
solution of
6-Chloro-2-[4-(4-chloro-benzyl)-4-cyano-piperidine-1-carbonyl]-2,3-dih-
ydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (230 mg,
0.45 mmol) in DCM at 5-10.degree. C. and the reaction mixture was
stirred for 2-4 h at room temperature. The solution was
concentrated and basified with 1 (N) NaOH solution. The aqueous
solution was extracted with ethyl acetate and the organic layer was
washed with water and brine solution. Concentration of the organic
layer afforded 140 mg (29%) of
4-(4-Chloro-benzyl)-1-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbon-
yl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+: 414.3.
.sup.1H-NMR (400MHz, DMSO-d.sub.6) .delta. (ppm): 7.34 (m, 2H),
7.19 (t, J=8.7 Hz, 2H), 6.69 (m, 1H), 6.58 (s, 1H), 6.47 (d, J=8.2
Hz, 1H), 6.18 (s, 1H), 4.92 (m, 1H), 4.39 (m, 1H), 4.07 (m, 1H),
3.40-2.67 (m, 6H), 1.88 (m, 3H), 1.55 (m, 1H). HPLC purity:
90.80%
Example 32
[4-(4-Chloro-benzyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-(6-chloro-3,4--
dihydro-2H-benzo[1,4]oxazin-2-yl)-methanone
##STR00054## ##STR00055##
[0582] 6-Chloro-2,3-dihydro-benzo[1,4]oxazine -2,4-dicarboxylic
acid 4-tert-butyl ester was prepared as described in Example 8.
Step-1: 3,3-Dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl
ester
[0583] Methyl iodide (11.8 ml, 0.19 mol) was added at 0.degree. C.
to a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl
ester (18 g, 0.09 mol). Sodium tert butoxide (20.9 g, 0.22 mol) was
then added at 0.degree. C. and the resulting mixture was heated to
reflux for 1 hour. The reaction mixture was concentrated under
reduced pressure, diluted with water and the product was extracted
with ethyl acetate. The organic layer was washed with brine, dried
over sodium sulfate and concentrated Purification of the residue by
column chromatography (2% ethyl acetate-hexane) afforded 7 g (37%)
of 3,3-dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl
ester. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 3.7 (m,
2H), 3.41 (m, 2H), 2.47 (t, 2H), 1.48 (s, 9H), 1.09 (s, 6H).
Step-2:
4-(4-Chloro-benzyl)-4-hydroxy-3,3-dimethyl-piperidine-1-carboxyli-
c acid tert-butyl ester
[0584] Magnesium turnings (500 mg, 20.57 mmol) were added to a
solution of 4-chlorobenzyl bromide (3.52 g, 17.2 mmol) in ether and
the mixture was stirred at room temperature for 1 hour. A solution
of 3,3-dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester
(3.0 g, 13.2 mmol) in THF was then added dropwise at room
temperature and the mixture was heated to reflux overnight. The
mixture was then diluted with aqueous saturated NH4Cl solution and
extracted with ethyl acetate. The organic layer was washed with
water, dried over sodium sulfate, concentrated and purified through
Si-gel (5% ether-hexane) to afford 1.8 g (38.5%) of
4-(4-chloro-benzyl)-4-hydroxy-3,3-dimethyl-piperidine-1-carboxylic
acid tert-butyl ester. LC/MS [M+H].sup.+: 354.3
Step-3: 4-(4-Chloro-benzyl)-3,3-dimethyl-piperidin-4-ol
[0585] Trifluoroacetic acid (3.8 ml, 50 mmol) was added to a
solution of
4-(4-chloro-benzyl)-4-hydroxy-3,3-dimethyl-piperidine-1-carboxylic
acid tert-butyl ester (1.8 g, 5.08 mmol)) in DCM and the resulting
mixture was stirred for about 5 h. The reaction mass was
concentrated and washed with dry ether. The TFA salt was diluted
with a minimum volume of water and neutralized with aq. NaOH
solution at 5-10.degree. C. Extraction of the neutralized solution
followed by concentration afforded 1 g (77.6%) of
4-(4-chloro-benzyl)-3,3-dimethyl-piperidin-4-ol. LC/MS [M+H].sup.+:
254.2
Step-4:
6-Chloro-2-[4-(4-chloro-benzyl)-4-hydroxy-3,3-dimethyl-piperidine-
-1-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester
[0586] To a solution of 6-chloro-2,3-dihydro-benzo[1,4]oxazine
-4-carboxylic acid tert-butyl ester-2-carboxylic acid (150 mg, 0.48
mmol) in DMF was added
4-(4-chloro-benzyl)-3,3-dimethyl-piperidin-4-ol (121 mg, 0.48
mmol), EDCI (275 mg, 1.43 mmol), HOBt (33 mg, 0.24 mmol) and DIPEA
(0.28 ml, 1.67 mmol) at 5-10.degree. C. and the mixture was stirred
at room temperature for 14-16 hours. The mixture was then diluted
with water and extracted with ethyl acetate. The organic layer was
concentrated under reduced pressure and purification of the residue
by flash chromatography (silica-gel, 2% MeOH-DCM) afforded 110 mg
(42%) of
6-chloro-2-[4-(4-chloro-benzyl)-4-hydroxy-3,3-dimethyl-piperidine-1-carbo-
nyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester. LC/MS [M+H].sup.+: 549.4. .sup.1H-NMR (400MHz, DMSO-d.sub.6)
.delta. (ppm): 7.85 (m, 1H), 7.31 (m, 2H), 7.11 (m, 2H), 6.93 (m,
1H), 6.83 (m, 1H), 4.85 (m, 1H), 4.35 (m, 1H), 3.71 (m, 2H), 2.90
(m, 1H) 2.64 (m, 1H), 1.77 (m, 1H), 1.54 (s, 9H), 1.26 (m, 1H),
1.06 (m, 6H), 1.03 (m, 2H).
Step-5:
[4-(4-Chloro-benzyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-(6-ch-
loro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-methanone
[0587] Trifluoroacetic acid (1.4 ml, 2.0 mmol) was added at
5-10.degree. C. to a solution of
6-chloro-2-[4-(4-chloro-benzyl)-4-hydroxy-3,3-dimethyl-piperidine-1-carbo-
nyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester (100 mg, 0.2 mmol) in DCM. The resulting mixture was stirred
for 2-4 h at room temperature, then concentrated and basified with
1 (N) NaOH solution. The aqueous solution was extracted with ethyl
acetate and the organic layer was washed with water and brine
solution. Concentration of the organic layer afforded 65 mg (72.5%)
of
[4-(4-chloro-benzyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-(6-chloro-3,4-
-dihydro-2H-benzo[1,4]oxazin-2-yl)-methanone. LC/MS [M+H].sup.+:
449.3. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.29 (m,
4H), 6.67 (m, 1H), 6.61 (s, 1H), 6.47 (m, 1H), 5.92 (br s, 1H),
3.99 (s, 1H), 3.77 (m, 1H), 3.35 (m, 4H), 2.82 (d, 1H), 2.68 (m,
1H), 1.61 (m, 1H), 1.18 (d, 1H), 0.86 (m, 1H), 0.82 (m, 6H). HPLC
purity: 98.2%
Example 33
4-(4-Chloro-benzyl)-1-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl-
)-3,3-dimethyl-piperidin-4-ol
##STR00056##
[0589] To a solution of
[4-(4-chloro-benzyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-(6-chloro-3,4-
-dihydro-2H-benzo[1,4]oxazin-2-yl)-methanone (prepared as described
in Example 32) (30 mg, 0.07 mmol) in THF was added BH.sub.3-DMS
(0.03 ml, 0.33 mmol) at 0.degree. C. The reaction mixture was
stirred overnight at room temperature. The mixture was cooled to
0.degree. C., quenched with MeOH then heated to reflux for 1 h.
Concentration under reduced pressure followed by purification by
flash chromatography (silica-gel, 0-0.5% MeOH-DCM) afforded 20 mg
(67%) of
4-(4-chloro-benzyl)-1-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethy-
l)-3,3-dimethyl-piperidin-4-ol. LC/MS [M+H].sup.+: 435.2.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.26 (m, 4H),
6.61 (d, J=8.28, 1H), 6.55 (d, J=1.76 , 1H) 6.42 (dd, 1H), 6.06 (s,
1H), 4.06 (d, 1H), 3.87 (s, 1H), 3.00 (q, 1H), 2.72 (d, 1H), 2.63
(m, 1H), 2.42 (m, 2H), 2.13 (m, 1H), 1.53 (m, 1H), 1.05 (s, 3H),
0.88 (s, 3H). HPLC purity: 98.8%
Example 34
[4-(4-Chloro-benzyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-(6-chloro-2,3--
dihydro-benzo[1,4]dioxin-2-yl)-methanone
##STR00057##
[0591] 4-(4-Chloro-benzyl)-3,3-dimethyl-piperidin-4-ol was prepared
as described in Example 32.
[0592]
[4-(4-Chloro-benzyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-(6-chlo-
ro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanone was prepared using
4-(4-Chloro-benzyl)-3,3-dimethyl-piperidin-4-ol coupling with
6-Chloro-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid by a
procedure similar to that described in Example 1. LC/MS
[M+H].sup.+: 450.2. .sup.1H-NMR (400MHz, DMSO-d.sub.6) .delta.
(ppm):7.31-6.87 (m, 7H), 5.31 (m, 1H), 4.36 -3.37 (m, 5H),
3.06-2.08 (m, 5H), 1.23 (m, 1H), 0.94 (s, 6H). HPLC purity:
93.1%
Example 35
4-(4-Chloro-benzyl)-1-(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-
,3-dimethyl-piperidin-4-ol
##STR00058##
[0594] To a solution of
[4-(4-chloro-benzyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-(6-chloro-2,3-
-dihydro-benzo[1,4]dioxin-2-yl)-methanone (40 mg, 0.09 mmol) in THF
was added BH.sub.3-DMS (0.04 ml, 0.44 mmol) at 0.degree. C. The
reaction mixture was stirred overnight at room temperature. The
reaction mixture was then cooled to 0.degree. C., quenched with
MeOH and the solution was heated to reflux for 1 h. The reaction
mixture was concentrated under reduced pressure. Purification of
the residue by flash chromatography (silica-gel, 2.5% EtOAc-hexane)
afforded 20 mg (51%) of
4-(4-chloro-benzyl)-1-(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)--
3,3-dimethyl-piperidin-4-ol. LC/MS [M+H].sup.+:436.3 .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. (ppm): 7.27-6.74 (m, 7H), 4.33-3.93
(m, 3H), 2.89-2.16 (m, 10H), 1.15 (s, 3H), 0.99 (s, 3H). HPLC
purity: 96.2%
Example 36
1-(6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl-
)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00059##
[0595] Step-1:
6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester
[0596] Anhydrous K.sub.2CO.sub.3 (458 mg, 3.3 mmol) and methyl
iodide (0.2 ml, 3.3 mmol) were added to a solution of
6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester (prepared as described in Example 27) (300 mg, 1.1
mmol) in DMF and the resulting mixture was stirred at 40.degree. C.
for 3 hours. The mixture was diluted with crushed ice and extracted
with ethyl acetate. The organic layer was concentrated and purified
through column chromatography over Si-gel (7% ethyl acetate-hexane)
to afford 167 mg (53%) of
6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-c-
arboxylic acid ethyl ester. LC/MS [M+H].sup.+: 286.2
Step-2:
6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-ca-
rboxylic acid
[0597] Lithium hydroxide (48 mg, 1.15 mmol) was added to a solution
of
6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester (165 mg, 0.58 mmol) in THF:H.sub.2O (2:1) and the
resuling mixture was stirred for 5-6 h, then concentrated the crude
product was neutralized with 50% aqueous acetic acid and extracted
with ethyl acetate. Concentration of ethyl acetate layer afforded
110 mg (74%) of
6-chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxy-
lic acid. LC/MS [M+H].sup.+: 258.4
Step-3:
1-(6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-
-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0598] To a solution of
6-chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid (110 mg, 0.43 mmol) in DMF was added
4-(4-Chloro-benzyl)-piperidine-4-carbonitrile (93 mg, 0.0.43 mmol),
EDCI (106 mg, 0.55 mmol), HOBt (29 mg, 0.22 mmol) and DIPEA (0.15
ml, 0.85 mmol) at 5-10.degree. C. and the mixture was stirred at
room temperature for 14-16 hours. The reaction mixture was diluted
with water and extracted with ethyl acetate. The organic layer was
concentrated under reduced pressure and the residue was purified by
flash chromatography (silica-gel, 2% MeOH-DCM) to afford 145 mg
(75%) of
1-(6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbony-
l)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS
[M+H].sup.+: 458.3. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.35-6.59 (m, 7H), 5.2 (br s, 1H), 4.38 (m, 1H), 4.08 (m,
1H), 3.72 (s, 3H), 3.27-3.12 (m, 3H), 2.96 (s, 2H), 2.77 (s, 3H),
2.68 (m, 1H), 1.86-1.23 (m, 4H). HPLC purity: 91.4%
Example 37
1-(6-Chloro-7-hydroxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile
##STR00060## ##STR00061##
[0599] Step-1: 2-chloro-5-fluoro-4-nitro-phenol
[0600] Ferric nitrate nonahydrate (14.06 g, 34.12 mmol) was added
to a solution of 2-chloro-5-fluoro-phenol (5 g, 34.12 mmol) in and
the resulting mixture was stirred at 55.degree. C. for 5 hours. The
mixture was then diluted with water and extracted with chloroform.
The organic layer was concentrated and and crude product was
recrystallized from toluene and heptane to afford 2 g (38%) of
2-chloro-5-fluoro-4-nitro-phenol. .sup.1H-NMR (400MHz, CDCl.sub.3)
.delta. (ppm): 8.19 (d, J=7.64 Hz, 1H), 6.93 (d, J=11.4 Hz, 1H),
6.42 (br s, 1H).
Step-2: 4-benzyloxy-5-Chloro-2-fluoro-nitrobenzene
[0601] K.sub.2CO.sub.3 (0.87 g, 6.26 mmol) and benzyl bromide (0.62
ml, 5.22 mmol) were added to a solution of
2-chloro-5-fluoro-4-nitro-phenol (1 g, 5.22 mmol) in DMF and the
resulting mixture was stirred at room temperature for 2 hours. The
reaction mixture was then diluted with water and extracted with
ethyl acetate. The organic layer was concentrated and purified
through column chromatography over Si-gel (1% EtOAC-hexane) to
afford 1.1 g (76%) of 4-benzyloxy-5-Chloro-2-fluoro-nitrobenzene.
GCMS [m/z]:281
Step-3: 5-Benzyloxy-4-chloro-2-nitrophenol
[0602] NaOH (475 mg, 11.1 mmol) was added to
4-benzyloxy-5-chloro-2-fluoro-nitrobenzene (220 mg, 0.79 mmol) in
water and the solution was heated to reflux overnight. The reaction
mixture was then diluted with water and adjusted to pH 3-4. The
solution was extracted with ethyl acetate, which was washed with
water and dried over sodium sulfate. Concentration of the organic
layer afforded 100 mg (45%) of 5-benzyloxy-4-chloro-2-nitrophenol.
GCMS [m/z]:279
Step-4: 2-Amino-5-benzyloxy-4-chlorophenol
[0603] SnCl.sub.2.2H.sub.2O (5.65 g, 25 mmol) was added to a
solution of 5-benzyloxy-4-chloro-2-nitrophenol (1.4 g, 5.0 mmol) in
ethanol and the resulting mixture ws heated to reflux for 5 hours.
The mixture was basified and extracted with ethyl acetate. The
organic layer was washed with water and dried over sodium sulfate.
Concentration of organic layer afforded 975 mg (78%) of
2-amino-5-benzyloxy-4-chlorophenol. LC/MS [M+H].sup.+: 250.4
Step-5:
7-Benzyloxy-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxyli-
c acid ethyl ester
[0604] 2,3-Dibromo-ethylpropiolate (0.67 ml, 4.68 mmol) and
K.sub.2CO.sub.3 (1.5 g, 10.84 mmol) were added to
2-amino-5-benzyloxy-4-chlorophenol (970 mg, 3.9 mmol) in acetone
and the resulting mixture was heated to reflux overnight. The
reaction mixture was concentrated and purified through column
chromatography over Si-gel (12% EtOAC-hexane) to afford 600 mg
(45%) of
7-Benzyloxy-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester. LC/MS [M+H].sup.+: 348.3
Step-6:
7-Benzyloxy-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxyl-
ic acid 4-tert-butyl ester 2-ethyl ester
[0605] DMAP (21 mg, 0.17 mmol) and (Boc).sub.2O (3.8 ml, 17.3 mmol)
were added to a solution of
7-Benzyloxy-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester (600 mg, 1.73 mmol) in THF and the resulting
mixture was heated to reflux overnight. The mixture was then
concentrated, diluted with water and extracted with ethyl acetate.
The organic layer was dried over sodium sulfate and concentrated
under reduced pressure. The crude product was purified through
column chromatography over Si-gel (6%-ethyl acetate-hexane) to
afford 1.7 g (75%) of
7-Benzyloxy-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester. .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 7.80 (br s, 1H), 7.45-7.28 (m, 5H), 6.63
(s, 1H), 5.08 (m, 2H0, 4.79 (t, 1H0, 4.22 (m, 3), 3.77 (m, 1H),
1.51 (s, 9H), 1.26 (t, 3H).
Step-7:
7-Benzyloxy-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxyl-
ic acid 4-tert-butyl ester
[0606] Lithium hydroxide (150 mg, 3.57 mmol) was added to a
solution of
7-Benzyloxy-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester (800 mg, 1.79 mmol) in
THF:H.sub.2O (2:1) and the resulting mixture was stirred for 5-6 h,
then concentrated. The crude product was neutralized with 50%
aqueous acetic acid and extracted with ethyl acetate. Concentration
of the ethyl acetate layer afforded 550 mg (76%) of
7-Benzyloxy-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
(ppm): 7.80 (br s, 1H), 7.45-7.31 (m, 5H), 6.63 (s, 1H), 5.08 (m,
2H), 4.84 (m, 1H), 4.14 (m, 1H), 3.90 (m, 1H), 1.50 (s, 9H).
Step-8:
7-Benzyloxy-6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1--
carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester
[0607] To a solution of
ethyl-7-benzyloxy-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester-2-carboxylic acid (550 mg, 1.3 mmol) in DMF
was added 4-cyano-4-(4-fluoro-benzyl)-piperidine (286 mg, 1.31
mmol), EDCI (380 mg, 1.97 mmol), HOBt (212 mg, 1.57 mmol) and DIPEA
(0.68 ml, 3.93 mmol) at 5-10.degree. C. and the mixture was stirred
at room temperature for 14-16 hours. The reaction mixture was then
diluted with water and extracted with ethyl acetate. The organic
layer was concentrated under reduced pressure and the residue was
purified by flash chromatography (silica-gel, 2% MeOH-DCM) to
afford 795 mg (98%) of
7-benzyloxy-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl-
]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester.LC/MS [M+H].sup.+: 620.5
Step-9:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-l-carbonyl]-7--
hydroxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester
[0608]
7-benzyloxy-6-chloro-2[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-car-
bonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester (790 mg) was hydrogenated with 5% Pd-C (40 mg) in ethyl
acetate for 2 h. The catalyst was removed by filtration through a
celite bed. Concentration of the ethyl acetate solution yielded 650
mg (96.3%) of
6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-hydroxy--
2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester.
LC/MS [M+H].sup.+: 530.4
Step-10:
1-(6-Chloro-7-hydroxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbony-
l)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0609] Trifluoroacetic acid (0.1 ml, 1.33 mmol) was added to
6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-hydroxy--
2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
(70 mg, 0.13 mmol) in DCM at 5-10.degree. C. and the reaction
mixture was stirred for 2-4 h at room temperature. The solution was
then concentrated and neutralised with 1 (N) NaOH solution. The
product was extracted with ethyl acetate and the organic layer was
washed with water and brine solution. The organics were
concentrated and purified through column chromatography over Si-gel
(2% MeOH-DCM) to afford 20 mg (36%) of
1-(6-chloro-7-hydroxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-f-
luoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+: 430.2.
.sup.1N-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 9.16 (s, 1H),
7.34 (br s, 2H), 7.19 (m, 2H), 6.50 (s, 1H), 6.39 (s, 1H), 5.39 (s,
1H), 4.90 (br s, 1H), 4.38 (br s, 1H), 4.07 (br s, 1H), 3.17 (m,
2H), 2.96 (s, 2H), 2.67 (m, 1H), 1.81 (m, 3H), 1.54 (m, 1H). HPLC
purity: 96.1%
Example 38
{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,
4-dihydro-2H-benzo[1,4]oxazin-7-yloxy}-acetic acid
##STR00062##
[0610] Step-1:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-methoxyc-
arbonylmethoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester
[0611] K.sub.2CO.sub.3 (156 mg, 1.13 mmol) and methyl bromoacetate
(0.57 ml, 0.63 mmol) were added to
6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-hydroxy--
2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
(300 mg, 0.57 mmol) in DMF. The resulting mixture was stirred at
room temperature for 3 hours then diluted with water. The resulting
precipitate was filtered, washed with water and the residue was
dissolved in ethyl acetate. The organic layer was concentrated to
afford 315 mg (92.7%) of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-methoxyc-
arbonylmethoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester. LC/MS [M+H].sup.+: 602.4
Step-2:
7-Carboxymethoxy-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidi-
ne-1-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester
[0612] Lithium hydroxide (20 mg, 0.37 mmol) was added to a solution
of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-methoxyc-
arbonylmethoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester (90 mg, 0.15 mmol) in THF:H.sub.2O (2:1) and the
mixture was stirred for 5-6 h. After concentrating the mixture, the
crude product was neutralized with 50% aqueous acetic acid and
extracted with ethyl acetate. Concentration of the ethyl acetate
layer afforded 65 mg (79%) of
7-Carboxymethoxy-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-car-
bonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester. LC/MS [M+H].sup.+: 588.2
Step-3:
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-
-3,4-dihydro-2H-benzo[1,4]oxazin-7-yloxy}-acetic acid
[0613] Trifluoroacetic acid (0.1 ml, 1.33 mmol) was added to
7-Carboxymethoxy-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-car-
bonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester (65 mg, 0.11 mmol) in DCM at 5-10.degree. C. and the reaction
mixture was stirred for 2-4 h at room temperature. The solution was
concentrated and neutralised with 1 (N) NaOH solution. The product
was extracted with ethyl acetate/EtOH and the organic layer was
washed with water and brine solution. Concentration of the organic
layer afforded 35 mg (65.2%) of
2-{6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dih-
ydro-2H-benzo[1,4]oxazin-7-yloxy}-acetic acid. LC/MS [M+H].sup.+:
488.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.42-7.17
(m, 6H), 6.64 (s, 1H), 6.55 (m, 1H), 5.69 (br s, 1H), 4.97 (m, 1H),
4.36 (s, 2H), 4.03 (m, 2H), 3.21 (m, 2H), 2.95 (s, 2H), 2.67 (m,
1H), 1.80-1.54 (m, 4H). HPLC purity: 90.7%
Example 39
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dihy-
dro-2H-benzo[1,4]oxazin-7-yloxy}-acetamide
##STR00063##
[0614] Step-1:
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dih-
ydro-2H-benzo[1,4]oxazin-7-yloxy}-acetamide-4-carboxylic acid tert
butyl ester
[0615] A solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-methoxyc-
arbonylmethoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester (100 mg) in methanol was saturated with ammonia by
purging with ammonia gas at atmospheric pressure at -5.degree. C.
The resulting mixture was heated at 70.degree. C. in a sealed tube
overnight. The mixture was then concentrated to afford 70 mg
(71.4%) of
2-{6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dih-
ydro-2H-benzo[1,4]oxazin-7-yloxy}-acetamide-4-carboxylic acid tert
butyl ester. LC/MS [M+H].sup.+: 587.2
Step-2:
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-
-3,4-dihydro-2H-benzo[1,4]oxazin-7-yloxy}-acetamide
[0616] Trifluoroacetic acid (0.1 ml, 1.33 mmol) was added to
2-{6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dih-
ydro-2H-benzo[1,4]oxazin-7-yloxy}-acetamide-4-carboxylic acid tert
butyl ester (50 mg, 0.085 mmol) in DCM at 5-10.degree. C. and the
resulting mixture was stirred for 2-4 h at room temperature. The
solution was concentrated and neutralised with 1 (N) NaOH solution.
The product was extracted with ethyl acetate/EtOH and the organic
layer was washed with water and brine solution. Concentration of
the organic layer afforded 30 mg (73.2%) of
2-{6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dih-
ydro-2H-benzo[1,4]oxazin-7-yloxy}-acetamide.LC/MS [M+H].sup.+:
487.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.38-7.17
(m, 4H), 6.58 (s, 1H), 6.35 (s, 1H), 5.42 (s, 1H), 4.91 (br s, 1H),
4.38 (m, 1H), 4.09 (m, 2H), 4.02 (s, 2H), 3.19-2.60 (m, 6H), 1.78
(m, 2H). HPLC purity: 92.7%
Example 40
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dihy-
dro-2H-benzo[1,4]oxazin-7-yloxy}-N,N-dimethyl-acetamide
##STR00064##
[0617] Step-1:
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dih-
ydro-2H-benzo[1,4]oxazin-7-yloxy}-N,N-dimethyacetamide-4-carboxylic
acid tert butyl ester
[0618]
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-me-
thoxycarbonylmethoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester (80 mg, 0.133 mmol) was heated in a THF
solution of dimethylamine at 70.degree. C. in a sealed tube
overnight. Concentration of the reaction mixture afforded 80 mg
(97.8%) of
2-16-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dih-
ydro-2H-benzo[1,4]oxazin-7-yloxy}-N,N-dimethyacetamide-4-carboxylic
acid tert butyl ester. LC/MS [M+H].sup.+: 615.4
Step-2:
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-
-3,4-dihydro-2H-benzo[1,4]oxazin-7-yloxy}-N,N-dimethyacetamide
[0619] Trifluoroacetic acid (0.1 ml, 1.33 mmol) was added to
2-{6-chloro-2-[4-eyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dih-
ydro-2H-benzo[1,4]oxazin-7-yloxy}-N,N-dimethyacetamide-4-carboxylic
acid tert butyl ester (80 mg, 0.13 mmol) in DCM at 5-10.degree. C.
and the resulting mixture was stirred for 2-4 h at room
temperature. The solution was concentrated and neutralised with 1
(N) NaOH solution. The product was extracted with ethyl
acetate/EtOH and the organic layer was washed with water and brine
solution. Concentration of the organic layer afforded 50 mg (74.7%)
of
2-{6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dih-
ydro-2H-benzo[1,4]oxazin-7-yloxy}-N,N-dimethyacetamide. LC/MS
[M+H].sup.+: 515.4. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
(ppm): 7.30-6.55 (7H), 4.75 (br s, 1H), 4.66-3.32 (m, 8H), 3.09 (s,
3H), 2.96 (s, 3H), 2.86 (m, 3H), 1.90 (m, 2H), 1.73 (m, 1H).HPLC
purity: 95.2%
Example 41
1-(6-Chloro-7-ethoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-flu-
oro-benzyl)-piperidine-4-carbonitrile
##STR00065##
[0620] Step-1:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-ethoxy-2-
,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
[0621] Anhydrous K.sub.2CO.sub.3 (52 mg, 0.38 mmol) and ethyl
iodide (0.05 ml, 0.57 mmol) were added to
6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-hydroxy--
2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
(prepared as described in Example 37 (100 mg, 0.19 mmol) in acetone
and the resulting mixture was stirred at 50.degree. C. overnight.
The mixture was then diluted with crushed ice and extracted with
ethyl acetate. The organic layer was concentrated and purified
through column chromatography over Si-gel (20% ethyl
acetate-hexane) to afford 90 mg (85%) of
6-chloro-2-[4-cyano-4-(4-fluoro-benzyp-piperidine-1-carbonyl]-7-ethoxy-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester.
LC/MS [M+H].sup.+:558.2
Step-2:
1-(6-Chloro-7-ethoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-
-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0622] Trifluoroacetic acid (1 ml) was added to
6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-ethoxy-2-
,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (90
mg, 0.16 mmol) in DCM at 5-10.degree. C. and the reaction mixture
was stirred for 2-4 h at room temperature. The solution was then
concentrated and neutralised with 1 (N) NaOH solution. The product
was extracted with ethyl acetate/EtOH and the organic layer was
washed with water and brine solution. Concentration of organic
layer afforded 66 mg (75.8%) of
1-(6-chloro-7-ethoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+: 458.4.
.sup.1N-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.34-6.55 (6 Ar
H), 5.59 (s, 1H), 4.97 (m, 1H), 4.38 (m, 1H), 4.07 (m, 1H), 3.94
(t, 2H), 3.19 (m, 2H), 2.95 (s, 2H), 2.69 (m, 1H), 1.89-1.39 (m,
4H), 1.27 (m, 4H). HPLC purity: 98.8%
Example 42
1-[6-Chloro-4-(2-dimethylamino-acetyl)-7-methoxy-3,4-dihydro-2H-benzo[1,4]-
oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00066##
[0624]
1-[6-Chloro-4-(2-dimethylamino-acetyl)-7-methoxy-3,4-dihydro-2H-1-b-
enzo[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
was prepared from
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-f-
luoro-benzyl)-piperidine-4-carbonitrile using a similar procedure
to that described in Example 18.LC/MS [M+H].sup.+: 529.3.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 8.04-6.69 (6 Ar
H), 5.40 (m, 1H), 4.44-4.00 (m, 3H), 3.81 (s, 3H), 3.21-2.23 (m,
8H), 2.19 (s, 6H), 1.87-1.54 (m, 4H). HPLC purity: 92.4%
Example 43
1-(4-Acetyl-6-chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl-
)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00067##
[0626]
1-(4-Acetyl-6-chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-c-
arbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared
from
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-f-
luoro-benzyl)-piperidine-4-carbonitrile using a similar procedure
to that described in Example 15. LC/MS [M+H].sup.+: 486.3.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 7.25-7.02 (m, 5H),
6.59 (s, 1H), 5.12 (s, 1H), 4.60 (d, J=14.4 Hz, 1H), 4.45 (m, 1H),
3.85 (s, 3H), 3.78 (m, 2H), 3.44 (m, 2H), 2.87 (m, 3H), 2.26 (s,
3H), 1.95 (m, 3H). HPLC purity: 95.1%
Example 44
1-[4-(4-Chloro-benzyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-2-(6-chloro--
3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-ethanone
##STR00068##
[0628] 4-(4-Chloro-benzyl)-3,3-dimethyl-piperidin-4-ol was prepared
as described in Example 32.
[0629]
1-[4-(4-Chloro-benzyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-2-(6--
chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-ethanone using a
similar procedures to that described in Example 25. LC/MS
[M+H].sup.+: 463.3. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.31-7.24 (m, 4H), 6.61-6.43 (m, 3H), 6.08 (s, 1H), 4.36 (m,
1H), 4.21-2.61 (m, 10H), 1.60-1.23 (m, 2H), 0.92 (s, 6H). HPLC
purity: 93.7%
Example 45
4-(4-Chloro-benzyl)-1-[2-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-e-
thyl)-3,3-dimethyl-piperidin-4-ol
##STR00069##
[0631]
4-(4-Chloro-benzyl)-1-[2-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin--
2-yl)-ethyl]-3,3-dimethyl-piperidin-4-ol was prepared from
1-[4-(4-Chloro-benzyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-2-(6-chloro-
-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-ethanone using a similar
procedures to that described in Example 30. LC/MS [M+H].sup.+:
449.3. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.29-7.23
(m, 4H), 6.62-6.41 (m, 3H), 6.08 (s, 1H), 3.98-1.51 (m, 16H), 1.02
(s, 3H), 0.90 (s, 3H). HPLC purity: 97.6%
Example 45A
1-[2-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-ethyl]-4-(4-fluoro-be-
nzyl)-3,3-dimethyl-piperidin-4-ol
##STR00070##
[0633]
1-[2-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-ethyl]-4-(4-fl-
uoro-benzyl)-3,3-dimethyl-piperidin-4-ol was prepared using a
similar procedure to that described in Example 45. LC/MS
[M+H].sup.+: 433.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.24 (m, 2H), 7.05 (m, 2H), 6.60 (d, 1H), 6.54 (m, 1H), 6.41
(d, 1H), 6.07 (br s, 1H), 3.99-1.68 (m, 16H), 1.03 (s, 3H), 0.90
(s, 3H). HPLC purity: 97.7%.
Example 46
1-(6-Chloro-4-methanesulfonyl-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-
-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00071##
[0635]
1-(6-Chloro-4-methanesulfonyl-7-methoxy-3,4-dihydro-2H-benzo[1,4]ox-
azine-2-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was
prepared from
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-f-
luoro-benzyl)-piperidine-4-carbonitrile using a similar procedures
to that described in Example 16. LC/MS [M+H].sup.+: 522.4.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 7.59-6.52 (6 Ar
H), 4.95 (m, 1H), 4.65 (m, 1H), 4.10 (m, 3H), 3.86 (s, 3H), 3.60
(m, 1H), 3.49 (m, 3H), 2.96 (s, 3H), 1.96 (m, 3H), 1.67 (m, 1H).
HPLC purity: 90.2%
Example 47
N-[7-(4-Chloro-benzyl)-piperidin-4-yl]-2-(6-chloro-3,4-dihydro-2H-benzo[1,-
4]oxazin-2-yl)-acetamide
##STR00072##
[0637]
2-Carboxymethyl-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester was prepared as described in Example 25.
[0638] 1-(4-Chloro-benzyl)-piperidin-4-ylamine was prepared using a
procedure similar to that described in Example 22.
[0639]
N-[1-(4-Chloro-benzyl)-piperidin-4-yl]-2-(6-chloro-3,4-dihydro-2H-b-
enzo[1,4]oxazin-2-yl)-acetamide was prepared from
1-(4-Chloro-benzyl)-piperidin-4-ylamine following amide coupling
with
2-Carboxymethyl-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester with 1-(4-Chloro-benzyl)-piperidin-4-ylamine
followed by deboc with TFA using a procedure similar to that
described in Example 25. LC/MS [M+H].sup.+: 434.2. .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. (ppm): 7.89 (d, 1H), 7.38-7.29 (m, 4H),
6.59-6.42 (m, 4H), 6.10 (s, 1H), 4.29 (m, 1H), 3.51 (m, 1H), 3.42
(s, 2H), 2.98 (m, 1H), 2.70 (m, 2H), 2.45-2.32 (m, 3H), 1.2.0 (t,
2H), 1.70 (m, 2H), 1.37 (m, 2H). HPLC purity: 99.1%
Example 48
[1-(4-Chloro-benzyl)-piperidin-4-yl]-[2-(6-chloro-3,4-dihydro-2H-benzo[1,4-
]oxazin-2-yl)-ethyl]-amine
##STR00073##
[0641]
[1-(4-Chloro-benzyl)-piperidin-4-yl]-[2-(6-chloro-3,4-dihydro-2H-be-
nzo[1,4]oxazin-2-yl)-ethyl]-amine was prepared from
N-[1-(4-Chloro-benzyl)-piperidin-4-yl]-2-(6-chloro-3,4-dihydro-2H-benzo[1-
,4]oxazin-2-yl)-acetamide using a procedure similar to that
described in Example 30. LC/MS [M+H].sup.+: 420.4. .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. (ppm): 7.36-7.28 (m, 4H), 6.61-6.54 (m,
2H), 6.42 (m, dd, 1H), 6.05 (s, 1H), 4.03 (m, 1H), 3.41 (s, 2H),
2.95 (m, 1H), 2.69 (m, 4H), 2.32 (m, 1H), 1.95 (t, 2H), 1.77-1.23
(m, 8H). HPLC purity: 97.6%
Example 49
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-methox-
y-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetamide
##STR00074##
[0643]
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared as
described in Example 27.
Step-1:
(6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-
-methoxy-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetic acid methyl
ester
[0644] Methyl bromoacetate (0.02 ml, 0.2 mmol) and K.sub.2CO.sub.3
(44.2 mg, 0.32 mmol) were added to a solution of
1-(6-chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-f-
luoro-benzyl)-piperidine-4-carbonitrile (70 mg, 0.16 mmol) in DMF
at 0.degree. C. and the resulting mixture was stirred overnight at
room temperature. The mixture was then diluted with ice-water and
the resulting precipitate was filtered and dried to afford 65 mg
(78.7%) of
[6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-methoxy-
-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetic acid methyl ester. LC/MS
[M+H].sup.+: 516.0
Step-2:
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-
-7-methoxy-2,3- dihydro-benzo[1,4]oxazin-4-yl}-acetamide
[0645] A solution of
{6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-methoxy-
-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetic acid methyl ester in
methanol was saturated with ammonia by purging with ammonia gas at
atmospheric pressure at -5 .degree. C. The resulting mixture was
heated overnight at 60.degree. C. The mixture was then concentrated
and washed with hexane to afford 30 mg (48%) of
2-{6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-metho-
xy-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetamide. LC/MS [M+H].sup.+:
501.4. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 8.18 (br s,
1H), 8.05 (br s, 1H), 7.24 (t, 2H), 7.04 (t, 2H), 6.57 (d, 1H),
6.47 (s, 1H), 5.37 (s, 1H), 4.95 (d, 1H), 4.53 (d, 1H), 4.34 (d,
1H), 3.79 (s, 3H), 3.72-1.89 (m, 10H). HPLC purity: 98.3%
Example 50
(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[(R)-4-(4-fluoro-
-benzyl)-2-methyl-piperazin-1-yl]-methanone
##STR00075##
[0647] (R)-1-(4-fluoro-benzyl)-3-methyl-piperazine was prepared as
described in Example 1.
[0648]
6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid was prepared as described in Example 27.
[0649]
(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[(R)-4-(4-
-fluoro-benzyl)-2-methyl-piperazin-1-yl]-methanone was prepared
from (R)-1-(4-fluoro-benzyl)-3-methyl-piperazine by amide coupling
with
6-chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid using a procedure similar to that described in Example 27.
LC/MS [M+H].sup.+: 434.3 .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
(ppm): 7.36 (t, 2H), 7.16 (t, 2H), 6.63-6.53 (m, 2H), 5.57 (br s,
1H), 4.88 (m, 1H), 4.49 (br s, 1H), 4.17 (m, 1H), 3.80 (m, 1H),
3.69 (s, 3H), 3.52-1.98 (m, 7H), 1.16 (d, 3H). HPLC purity:
99.5%.
Example 51
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00076##
[0651] 4-Cyano-4-(4-fluoro-benzyl)-piperidine was prepared as
described above in Example 23.
Step-1:
6-Chloro-7-nitro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
ethyl ester
[0652] NaNO.sub.3 (0.53 g, 6.2 mmol) was added to a solution of
6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid ethyl
ester (1 g, 4.1 mmol) in H.sub.2SO.sub.4 at -30.degree. C. and the
mixture was stirred at -30.degree. C. for 2 hour. The mixture was
then poured into ice-water and extracted with ethyl acetate. The
organic layer was washed with water and dried over sodium sulfate.
The organic layer was then concentrated and purified through Si-gel
column chromatography (7% ethyl acetate-hexane) to afford 350 mg
(30%) of
6-chloro-7-nitro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
ethyl ester. GCMS [m/z]:286.0
Step-2:
6-Chloro-7-nitro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester
[0653] DMAP (5 mg) and Boc.sub.2O (0.1 ml, 0.35 mmol) were added to
a solution of
6-chloro-7-nitro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
ethyl ester (100 mg, 0.35 mmol) in THF and the reaction mixture was
refluxed for 3 hours. After concentrating the mixture, the crude
product was purified through Si-gel column chromatography (3% ethyl
acetate-hexane) to afford 100 mg (74%) of
6-chloro-7-nitro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester. .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 8.04 (s, 1H), 7.66 (s, 1H), 4.91 (t,
1H), 4.48 (dd, 1H), 4.21 (m, 2H), 3.71 (dd, 1H), 1.27 (t, 3H).
Step-3:
7-Amino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester
[0654] Zn-powder (710 mg, 10.85 mmol) and NH.sub.4Cl (248 mg, 4.65
mmol) were added to a solution of
6-chloro-7-nitro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester (600 mg, 1.55 mmol) in
ethanol-water (4:1) and the mixture was heated to reflux for for 4
hours. The reaction mixture was then filtered through celite bed.
The organic layer was concentrated, diluted with water and the
product was extracted with ethyl acetate. The organic layer was
washed with water, dried over sodium sulfate and concentrated to
afford 450 mg (81.5%) of
7-amino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester. LC/MS [M+H].sup.+: 357.2
Step-4:
6-Chloro-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarb-
oxylic acid 4-tert-butyl ester 2-ethyl ester
[0655] K.sub.2CO.sub.3 (232 mg, 1.68 mmol) and methyl iodide (0.3
ml) were added to a solution of
7-amino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester (150 mg, 0.42 mmol) in DMF.
The reaction mixture was heated for 3 hour at 40.degree. C. then
diluted with water and extracted with ethyl acetate. The organic
layer was washed with water and dried over sodium sulfate. The
reaction mixture was concentrated and purified through Si-gel
column chromatography (6% ethyl acetate-hexane) to afford 45 mg
(28%) of
6-chloro-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester. LC/MS [M+H].sup.+: 385.2
Step-5:
6-Chloro-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarb-
oxylic acid 4-tert-butyl ester
[0656] LiOH (10 mg, 0.2 mmol) was added to a solution of
6-chloro-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester (70 mg, 0.18 mmol) in THF:
H.sub.2O (2:1) and the resuling solution was stirred for 3 hours.
The reaction mixture was concentrated and the crude product was
neutralized with 6(N) HCl solution and extracted with ethyl
acetate. Concentration of the ethyl acetate layer afforded 55 mg
(85.6%) of
6-chloro-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester. LC/MS [M+H].sup.+: 357.4
Step-6:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7--
dimethylamino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tent-butyl ester
[0657] To a solution
6-chloro-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (55 mg, 0.15 mmol) in DMF was added
4-(4-Fluoro-benzyl)-piperidine-4-carbonitrile (33.6 mg, 0.15
mmol)), EDCI (38.4 mg, 0.20 mmol), HOBt (10 mg, 0.07 mmol) and
DIPEA (01 ml, 0.4 mmol) at 5-10 .degree. C. and the mixture was
stirred at room temperature for 14-16 h. The mixture was then
diluted with water and extracted with ethyl acetate. The ethyl
acetate layer was concentrated in vacuo and subjected to column
chromatography (Si-gel, 1% MeOH-DCM) to afford 35 mg (41%)
6-chloro-2-[4-cyano-4-(4-fluoro-benzyp-piperidine-1-carbonyl]-7-dimethyla-
mino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester. LC/MS [M+H].sup.+: 557.4
Step-7:
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-ca-
rbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0658] Trifluoroacetic acid (0.5 ml) was added to a solution of
6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-dimethyl-
amino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester (35 mg, 0.06 mmol) in DCM and the resulting mixture was
stirred for 5 h. The mixture was then concentrated and washed with
dry ether. The TFA salt was diluted with a minimum volume of water
and neutralized with aq. NaOH solution at 5-10.degree. C. The
reaction mixture was extracted with ethyl acetate and washed with
water and brine solution. The organic layer was dried over sodium
sulfate and concentrated under reduced pressure to afford 18 mg
(62.7%) of
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
457.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.34 (br
s, 2H), 7.19 (m, 2H), 6.56 (br d, 2H), 4.92 (m, 1H), 4.38 (m, 1H),
4.03 (m, 1H), 3.19 (m, 2H), 2.88 (br s, 2H), 2.68 (m, 1H), 2.57 (s,
6H), 1.81-1.54 (m, 5H). HPLC purity: 89.1%
Example 52
N-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dihy-
dro-2H-benzo[1,4]oxazin-7-yl}-acetamide
##STR00077##
[0660] 4-Cyano-4-(4-fluoro-benzyl)-piperidine was prepared as
described above in Example 23.
[0661]
7-Amino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester was prepared as described in
Example 51.
Step 1:
7-Acetylamino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarbox-
ylic acid 4-tent-butyl ester 2-ethyl ester
[0662] Triethyl amine (0.13 ml, 0.91 mmol) and acetyl chloride
(0.03 ml, 0.4 mmol) were added to a solution of
7-amino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester (130 mg, 0.36 mmol) in THF at
10.degree. C. and the reaction mixture was stirred overnight. The
mixture was concentrated, diluted with water and extracted with
ethyl acetate. The organic layer was washed with water, dried over
sodium sulfate, concentrated and purified through Si-gel column
chromatography (6% ethyl acetate-hexane) to afford 60 mg (41%) of
7-acetylamino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester. LC/MS [M+H].sup.+: 399.2,
416.6 (M +17)
Step-2:
7-Acetylamino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarbox-
ylic acid 4-tert-butyl ester
[0663] LiOH (6 mg, 0.15 mmol) was added to a solution of
7-acetylamino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester (60 mg, 0.15 mmol) in
THF:H.sub.2O (2:1) and the mixture was stirred for 3 hours. The
mixture was then concentrated and the crude product was neutralized
with 50% acetic acid and extracted with ethyl acetate.
Concentration of the ethyl acetate layer afforded 35 mg (63%) of
7-acetylamino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester. LC/MS [M+H].sup.+: 371.4
Step-3:
7-Acetylamino-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine--
1-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tent-butyl ester
[0664] To a solution
7-acetylamino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (35 mg, 0.094 mmol) in DMF was added
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile (21 mg, 0.094 mmol)),
EDCI (27 mg, 0.14 mmol), HOBt (16 mg, 0.112 mmol) and DIPEA (0.05
ml, 0.28 mmol) at 5-10.degree. C. and the mixture was stirred at
room temperature for 14-16 h. The mixture was then diluted with
water and extracted with ethyl acetate. The ethyl acetate layer was
concentrated in vacuo and subjected to column chromatography
(Si-gel, 35% ethyl acetate-hexane) to afford 30mg (56%)
7-acetylamino-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbon-
yl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester. LC/MS [M+H].sup.+: 571.6
Step-4:
N-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-
-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl}-acetamide
[0665] Trifluoroacetic acid (0.5 ml) was added to a solution of
7-acetylamino-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbon-
yl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester (30 mg, 0.05 mmol) in DCM and the resulting mixture was
stirred for 5 h. The mixture was then concentrated and washed with
dry ether. The TFA salt was diluted with a minimum volume of water
and neutralized with aq. NaOH solution at 5-10.degree. C.
Extraction of the neutralized solution with ethyl acetate followed
by concentration afforded 18 mg (73.5%) of
N-{6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dih-
ydro-2H-benzo[1,4]oxazin-7-yl}-acetamide. LC/MS [M+H].sup.+: 471.4.
.sup.1H-NMR (400 MHz, CDCl3) .delta. (ppm): 7.81-6.65 (m, 7H), 4.77
(br s, 1H), 4.57 (m, 1H), 4.25 (m, 1H), 3.66 (m, 1H), 3.45 (m, 1H),
3.28 (m, 1H), 3.86 (br s, 2H), 2.19 (s, 3H), 2.03-1.40 (m, 6H).
HPLC purity: 99.6%
Example 53
(6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[(R)-4--
(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-methanone
##STR00078##
[0666] Step-1:
6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester
[0667] To a solution of
6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester (300 mg, 1.1 mmol) in DMF was added
K.sub.2CO.sub.3 (470 mg, 3.3 mmol) and methyl iodide (0.2 ml, 3.3
mmol) at 0.degree. C. The reaction mixture was stirred at 40
.degree. C. for 2 and half hours and diluted with water. The
organics was extracted with ethyl acetate, washed with water and
dried over anhd. Na.sub.2SO.sub.4. The organic layer was
concentrated and purified over column chromatography (Si-gel, 7%
ethyl acetate-hexane) to afford 167 mg (53%) of
6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester. LC/MS [M+H].sup.+: 286.2
Step-2: 6-Chloro-7-methoxy-4-methyl-3,
4-dihydro-2H-benzo[1,4]oxazine-2-carboxlic acid
[0668] To a solution of
6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester (165 mg, 0.58 mmol) in THF:H.sub.2O (2:1) was
added lithium hydroxide (48 mg, 1.15 mmol). The reaction mixture
was stirred for 5-6 h at rt and concentrated. The crude mass was
neutralized with 50% aqueous acetic acid and extracted with ethyl
acetate. Concentration of the ethyl acetate layer afforded 110 mg
(73.6%) of
6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid. LC/MS [M+H].sup.+: 258.4
Step-3:
(6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl-
)-[(R)-4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-methanone
[0669] To a solution of
6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid (50 mg, 0.19 mmol) in DMF was added
(R)-1-(4-Fluoro-benzyl)-3-methyl-piperazine (40.4 mg, 0.19 mmol),
EDCI (47.3 mg,0.25 mmol 1), HOBt (12.8 mg, 0.095 mmol) and DIPEA
(0.096 ml, 0.57 mmol) at 5-10.degree. C. The reaction mixture was
stirred at room temperature for 15 hours, diluted with water and
extracted with ethyl acetate. The ethyl acetate layer was
concentrated in vacuo and subjected to column chromatography
(Si-gel, 3% MeOH-DCM) to afford 35 mg (40%) of
(6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[(R)-4-
-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-methanone. LC/MS
[M+H].sup.+: 448.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm):7.28 (m, 2H), 7.00 (m, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 4.87
(brs, 1H), 4.69 (brs, 1H), 4.37 (m, 1H), 3.78 (s, 3H), 3.52-3.28
(m, 4H), 2.86 (s, 4H), 2.68-2.41 (m, 5H), 1.28 (m,3H). HPLC purity:
99.3%
Example 54
6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid [1-(4-fluoro-benzyl)-piperidin-4-yl]-amide
##STR00079##
[0670] Step-1: [1-(4-Fluoro-benzyl)-piperidin-4-yl]-carbamic acid
tert-butyl ester
[0671] To a solution of Piperidin-4-yl-carbamic acid tert-butyl
ester (1 g, 4.9 mmol) in THF was added triethyl amine (1.3 ml, 9.8
mmol) and 4-fluorobenzyl bromide (0.79 ml, 6.3 mmol) at ice-cold
condition. The reaction mixture was stirred at room temperature for
12 hrs and concentrated The reaction mass was diluted with water
and extracted with ethyl acetate. The organic layer was washed with
water, brine and dried over Na.sub.2SO.sub.4. The organic layer was
concentrated under reduced pressure and washed with hexane to
afford 500 mg (86.5%) of
[1-(4-Fluoro-benzyl)-piperidin-4-yl]-carbamic acid tert-butyl
ester.
[0672] LC/MS [M+H].sup.+: 309
Step-2: 1-(4-Fluoro-benzyl)-piperidin-4-ylamine
[0673] To a solution [1-(4-Fluoro-benzyl)-piperidin-4-yl]-carbamic
acid tert-butyl ester (1.4 g, 4.5 mmol) in DCM was added
trifluoroacetic acid (0.27 ml,3.61 mmol) drop wise at cold
condition. The mixture was allowed to stir at room temperature for
3 hours. Then reaction mixture was concentrated under reduced
pressure. The crude mass was diluted with water, basified with 2N
NaOH solution and extracted with ethyl acetate. The organic layer
was washed with water and brine, then dried over Na.sub.2SO.sub.4.
Concentration of the organic layer under reduced pressure afforded
700 mg (74.7%) of 1-(4-Fluoro-benzyl)-piperidin-4-ylamine.LC/MS
[M+H].sup.+: 209.4
Step-3:
6-Chloro-2-[1-(4-fluoro-benzyl)-piperidin-4-ylcarbamoyl]-7-methox-
y-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tent-butyl
ester
[0674] To a solution of 6-Chloro-7-methoxy-2,
3-dihydro-benzo[1,4]oxazine-2, 4-dicarboxylic acid-4-tert-butyl
ester (100 mg, 0.29 mmol) in DMF was added EDCI (72.49 mg, 0.37
mmol), HOBT (19.6 mg, 0.14 mmol) and DIPEA (0.16 ml, 0.87 mmol) at
0.degree. C. The resulting mixture was allowed to stir at room
temperature for 30 minutes. Then a solution of
1-(4-Fluoro-benzyl)-piperidin-4-ylamine in DMF was added to the
previous solution at 5.degree. C. The reaction mixture was allowed
to stir at rt overnight. The reaction mixture was diluted with
water and extracted with ethyl acetate. The organic layer was
concentrated under reduced pressure and the crude was purified by
column chromatography (Si-gel, 0.5% MeOH-DCM) to afford 60 mg
(38.7%) of
6-Chloro-2-[1-(4-fluoro-benzyl)-piperidin-4-ylcarbamoyl]-7-methoxy-2,
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester.
LC/MS [M+H].sup.+:534.4
Step-4: 6-Chloro-7-methoxy-3, 4-dihydro-2H-benzo[1,
4]oxazine-2-carboxylic acid
[1-(4-fluoro-benzyl)-piperidin-4-yl]-amide
[0675] To a solution of
6-Chloro-2-[1-(4-fluoro-benzyl)-piperidin-4-ylcarbamoyl]-7-methoxy-2,3-di-
hydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (50 mg,
0.09 mmol) in DCM was added trifluoroacetic acid (0.04 ml, 0.744
mmol) drop wise under ice-cold condition. The reaction mixture was
allowed to stir at room temperature for 3 hours. The reaction
mixture was concentrated and the crude mass was diluted with water,
basified with 2N NaOH solution and extracted with ethyl acetate.
Concentration of organic layer under reduced pressure afforded 9 mg
(22.3%) of 6-Chloro-7-methoxy-3,
4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
[1-(4-fluoro-benzyl)-piperidin-4-yl]-amide. LC/MS [M+H].sup.+:
434.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. (ppm) 7.77 (d,
1H), 7.30 (m, 2H), 7.13 (t, 2H), 6.86 (m, 2H), 5.60 (s, 1H), 4.44
(d, 1H), 3.68 (s, 3H), 3.59 (bs, 1H), 3.41 (s, 3H), 3.11 (m, 1H),
2.88 (m, 1H), 2.00 (m, 2H), 1.67 (m, 2H), 1.52 (m, 2H), 1.23 (bs,
1H). HPLC purity: 96.8%
Example 55
4-(4-Fluoro-benzyl)-1-(7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbon-
yl)-piperidine-4-carbonitrile
##STR00080## ##STR00081##
[0676] Step-1: 2-Amino-5-methoxy-phenol
[0677] A solution of 4-Chloro-5-methoxy-2-nitro-phenol (500 mg, 2.4
mmol) in ethyl acetate was hydrogenated overnight in presence of
10% Pd--C (50 mg). The catalyst was filtered off and ethyl acetate
solution was concentrated. The crude solid was washed with ether
and hexane to afford 260 mg (77.8%) of 2-amino-5-methoxyphenol.
LC/MS [M+H].sup.+: 140.
Step-2: 7-Methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester
[0678] To a solution of 2-amino-5-methoxyphenol (260 mg,1.86 mmol)
in acetone was added 2,3-dibromopropiobnate (0.28 ml,1.97 mmol)
drop wise and heated the reaction mixture with potassium carbonate
(692.7 mg,5.01 mmol) for 20 hours. The reaction mixture was
concentrated under reduced pressure and the crude was purified over
column chromatography (Si-gel, 6% EtOAC-hexane) to afford 120 mg
(27%) of 7-Methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester. GCMS (m/z): 237
Step-3: 7-Methoxy-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester
[0679] To a solution of 7-Methoxy-3, 4-dihydro-2H-benzo[1,
4]oxazine-2-carboxylic acid ethyl ester (120 mg, 0.51 mmol) in THF
was added catalytic amount (6.23 mg, 0.015 mmol) of DMAP and
stirred the solution for 5 hrs. The THF solution was concentrated
under reduced pressure and the crude was purified over column
chromatography (Si-gel, 6% EtOAC-hexane) to afford 100 mg (51%) of
7-Methoxy-2, 3-dihydro-benzo[1,4]oxazine-2, 4-dicarboxylic acid
4-tert-butyl ester 2-ethyl ester.
[0680] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. (ppm) 7.08-6.54
(m, 3Ar--H), 4.21 (m, 1H), 3.75 (s, 3H), 1.51 (m, 3H), 1.39 (m,
9H).
Step-4: 7-Methoxy-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester
[0681] To a solution of 7-Methoxy-2, 3-dihydro-benzo[1,4]oxazine-2,
4-dicarboxylic acid 4-tert-butyl ester 2-ethyl ester (90 mg, 0.27
mmol) in THF-water (3:1) was added LiOH.H.sub.2O (22.4 mg, 0.53
mmol) in cold condition. The mixture was allowed to stir at room
temperature for one and half hour. The reaction mixture was
concentrated, diluted with water, neutralized with AcOH and
extracted with ethyl acetate. The organic layer was washed with
water and brine, then dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure. The crude mass was washed with hexane to
afford 50 mg (60%) of solid 7-Methoxy-2,
3-dihydro-benzo[1,4]oxazine-2, 4-dicarboxylic acid 4-tert-butyl
ester.
Step-5:
2-[4-Cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-methoxy-2-
,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
[0682] To a solution of
7-Methoxy-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic acid
4-tert-butyl ester (40 mg, 0.13 mmol) in DMF was added EDCI (32.4
mg, 0.17 mmol), HOBT (8.8 mg, 0.065 mmol) and DIPEA (0.03 ml, 0.39
mmol) at 10.degree. C. The resulting mixture was allowed to stir at
room temperature for 30 minutes. Then a solution of
4-(4-Fluoro-benzyl)-piperidine-4-carbonitrile (28.4 mg, 0.13 mmol)
in DMF was added to the previous reaction mixture at 10.degree. C.
and the reaction mixture was allowed to stir at room temperature
overnight. The reaction mass was diluted with ice water, stirred
for 10 minutes and extracted with ethyl acetate. The organic layer
was washed with water and brine, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The crude organic mass was
purified over column chromatography (Si-gel, 6% EtOAC-hexane) to
afford 30 mg (44.6%) of
2-[4-Cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-methoxy-2,
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester.
LC/MS [M+H].sup.+: 510.4
Step-6:
4-(4-Fluoro-benzyl)-1-(7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-
-2-carbonyl)-piperidine-4-carbonitrile
[0683] To a solution of
2-[4-Cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-methoxy-2,3-dihyd-
ro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (30 mg,
0.053 mmol) in DCM was added trifluoroacetic acid (0.1 ml) drop
wise at cold condition. The mixture was allowed to stir at room
temperature for one and half an hour. The reaction mixture was
evaporated and the crude mass was diluted with water, basified with
2N NaOH solution and extracted with ethyl acetate. The organic
layer was washed with water and dried over Na.sub.2SO.sub.4.
Concentration of the organic extract under reduced pressure
afforded 4 mg (18%) of
4-(4-Fluoro-benzyl)-1(7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbon-
yl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+: 410.2.HPLC
purity: 87%
Example 56
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-methoxy-2-
,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid amide
##STR00082##
[0684]
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-me-
thoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid amide was
prepared from
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile by a process similar
to that described in example 11.LC/MS [M+H].sup.+: 487.3.
Example 57
1-(7-Bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fluo-
ro-benzyl)-piperidine-4-carbonitrile
##STR00083##
[0685] Step-1:
7-Bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
ethyl ester
[0686] To a stirred solution of
6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid ethyl
ester (41.38 m.mol,10.0 g) in acetic acid was added Br.sub.2 (41.38
m.mol,2.13 ml) drop wise at 10.degree. C. the reaction mixture was
stirred for 30 min at same temperature. The reaction mixture was
poured in ice-water, extracted the compound with ethyl acetate,
washed with water, brine, dried over Na.sub.2SO4 and concentrated
under reduced pressure. Thus obtained crude was purified through
column chromatography (Si-gel, 20% DCM-Hex) to afford 6.3 g (47.6%)
of 7-Bromo-6-chloro-3, 4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.(ppm)
7.13 (s, 1H), 6.67 (s, 1H), 4.77 (t, 1H), 4.22 (q, 2H), 3.85 (s,
1H), 3.56 (d, 2H), 1.26 (t, 3H).
Step-2:
7-Bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tent-butyl ester 2-ethyl ester
[0687] To a stirred solution of 7-Bromo-6-chloro-3,
4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid ethyl ester (4.5
g, 14.06 m.mol) in THF (30 ml), DMAP (0.172 g, 1.4 m.mol) and
(BOC).sub.2O (6.46 ml, 28.13 m.mol) were added and stirred the
reaction mixture overnight at room temperature. The reaction
mixture was concentrated and purified through column chromatography
(Si-gel, 3% EA/Hex) to afford 5.0 g (84.5%) of
7-Bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta.(ppm) 7.87-6.92 (m, 2H), 4.83 (t, 1H), 4.34
(dd, 1H), 4.21 (m, 2H), 3.70 (dd, 1H), 1.51 (s, 9H), 1.27 (t,
3H).
Step-3:
7-Bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid-4-tert-butyl ester
[0688] To a stirred solution of
7-Bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester(11.91 m.mol,5.0 g) in
THF:Water (3:1) was added LiOH (23.81 m.mol, 1.0 g) and stirred the
reaction mixture for 2 h at room temperature. The reaction mixture
was concentrated, diluted with water, acidified with dilute acetic
acid and extracted the organics with ethyl acetate. The organic
layer was washed with water, brine, dried over Na.sub.2SO4 and
concentrated under reduced pressure. Washed the crude with hexane
to afford 4.1 g (87.7%) of
7-Bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester. .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta.(ppm) 7.9-6.89 (m, 3H), 4.87-3.77 (m, 3H), 1.5 (s, 9H).
Step-4:
7-Bromo-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carb-
onyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester
[0689] To a solution of 7-Bromo-6-chloro-2,
3-dihydro-benzo[1,4]oxazine-2, 4-dicarboxylic acid 4-tert-butyl
ester (4.1 g, 10.5 m.mol) in DMF was added
4-(4-Fluoro-benzyl)-piperidine-4-carbonitrile (2.28 g, 10.5
m.mol,), EDCI (3.0 g, 15.7 m.mol), HOBt (1.69 g, 12.6 m.mol) and
DIPEA (5.4 ml, 31.4 m.mol) at 5-10.degree. C. The reaction mixture
was stirred at room temperature for 15 hours then diluted with
water. The precipitated solid was filtered and dried to afford 5.4
g (87.1%) of
7-Bromo-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester.
LCMS (M+H): 594.0. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.(ppm)
8.0-7.0 5 (m, 6H), 4.94-3.38 (m, 8H), 2.9 (s, 2H), 2.87 (m, 1H)
2.06-1.93 (m, 2H), 1.2 (s, 9H).
Step-5:
1-(7-Bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0690] To a solution of
7-Bromo-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (60
mg, 0.1 mmol) in DCM was added trifluoroacetic acid (0.3 ml, 3.9
mmol). The reaction mixture was stirred for about 5 h, concentrated
and washed with dry ether. The resulting TFA salt was diluted with
a minimum volume of water and neutralized with aq. NaOH solution at
5-10.degree. C. Extraction of the neutralized solution with ethyl
acetate followed by concentration under reduced pressure afforded
35 mg (71%) of
1-(7-Bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-flu-
oro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+: 493.3.
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.(ppm) 7.28 (m, 1H), 7.25
(m, 1H), 7.05 (m, 3H), 6.72 (m, 1H), 4.74 (m, 1H), 4.62 (m, 1H),
4.18 (m, 1H), 3.97 (m, 1H), 3.59 (m, 3H), 3.33 (m, 1H), 2.89 (m,
3H), 1.94-1.1.67 (m, 2H). HPLC purity: 90.5%.
Example 58
1-(6-Chloro-8-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00084## ##STR00085##
[0691] Step-1:
6-Chloro-8-nitro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
ethyl ester
[0692] NaNO.sub.3 (0.53 g, 6.2 mmol) was added to a solution of
6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid ethyl
ester (1 g, 4.1 mmol) in H.sub.2SO.sub.4 at -30.degree. C. and the
mixture was stirred at -30.degree. C. for 2 hour. The mixture was
then poured into ice-water and extracted with ethyl acetate. The
organic layer was washed with water, dried over sodium sulfate and
the organic layer was concentrated under reduced pressure and
purified through Si-gel column chromatography (5% ethyl
acetate-hexane) to afford 400 mg (28.2%) of
6-Chloro-8-nitro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
ethyl ester. GCMS (m/z): 286.0
[0693]
1-(6-Chloro-8-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared by
a similar method as described in example 51. LC/MS [M+H].sup.+:
457.0. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.(ppm) 7.22 (m,
2H), 7.03 (t, 2H), 6.29 (m, 2H), 4.67 (m, 2H), 4.32 (d, 1H), 3.85
(bs, 1H), 3.50 (m, 4H), 3.32 (m, 111), 2.89 (m, 1H), 2.73 (s, 6H),
1.92 (m, 2H), 1.75 (m, 1H), 0.86 (m, 1H). HPLC purity: 77%.
Example 59:
1-(6,7-Dichloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fluoro-b-
enzyl)-piperidine-4-carbonitrile
##STR00086##
[0694] Step-1:
6,7-Dichloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
ethyl ester
[0695] To a solution of
6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid ethyl
ester (200 mg, 0.83 mmol) in CCl.sub.4 was added N-Chloro
succinimide (116 mg,0.87 mmol) and AIBN (20 mg) at 0.degree. C. The
resulting mixture was allowed to stir at room temperature for 30
minutes and then refluxed for 3 hours. Then organic solution was
evaporated under reduced pressure. The crude was purified over
column chromatography (Si-gel, 2% ethyl acetate-hexane) to afford
50 mg (22%) of
6,7-Dichloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
ethyl ester. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.(ppm) 6.99
(s, 1H), 6.65 (s, 1H), 4.78 (t, 1H), 4.24 (m, 2H), 3.82 (s, 1H),
3.56 (s, 1H), 3.31 (t, 1H).
Step-2: 6,7-Dichloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester
[0696] To a solution of
6,7-Dichloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
ethyl ester (150 mg,0.54 mmol) in THF was added DMAP (6.6 mg, 0.05
mmol) and di-tert-butyl carbonate (0.62 ml, 2.72 mmol). The mixture
was allowed to reflux at 80.degree. C. overnight. The reaction
mixture was evaporated under reduced pressure. The crude was
purified over column chromatography (Si-gel, 2% ethyl
acetate-hexane) to afford 130 mg (64%) of
6,7-Dichloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic acid
4-tert-butyl ester 2-ethyl ester. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta.(ppm) 7.89 (s, 1H), 7.30 (s, 1H), 5.27 (bs,
1H), 4.46 (d, 1H), 4.12 (m, 1H), 3.57 (d, 1H), 1.46 (s, 9H).
Step-3: 6,7-Dichloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester
[0697] To a solution of 6, 7-Dichloro-2,
3-dihydro-benzo[1,4]oxazine-2, 4-dicarboxylic acid 4-tert-butyl
ester 2-ethyl ester (130 mg,0.35 mmol) in THF-water (3:1) was added
LiOH.H.sub.2O (17.4 mg, 0.41 mmol) in ice-cold condition. The
mixture was allowed to stir at room temperature during one and half
hour. The reaction mixture was evaporated and the crude mass was
diluted with water, neutralized with AcOH and extracted with ethyl
acetate. The organic layer was washed with water, brine and
concentrated under reduced pressure. The crude mass was washed with
hexane to afford 80 mg (66%) of 6, 7-Dichloro-2,
3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic acid 4-tert-butyl
ester. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.(ppm) 7.91 (bs,
1H), 7.26 (m, 1H), 7.16 (m, 1H), 5.07 (bs, 1H), 4.39 (d, 1H), 3.58
(d, 1H), 1.45 (s, 9H).
Step-4:
6,7-Dichloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl-
]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester
[0698] To a solution of
6,7-Dichloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic acid
4-tert-butyl ester (80 mg, 0.23 mmol) in DMF was added
4-cyano-4-(4-fluoro-benzyl)-piperidine (286 mg, 1.31 mmol), EDCI
(57.3 mg, 0.29 mmol), HOBT (15.5 mg, 0.11 mmol) and DIPEA (0.12 ml,
0.69 mmol) at 5-10.degree. C. and the mixture was stirred at room
temperature for 14-16 hours. The reaction mixture was then diluted
with water and extracted with ethyl acetate. The organic layer was
concentrated under reduced pressure and the residue was purified by
flash chromatography (silica-gel, 2% MeOH-DCM) to afford 300 mg
(59%) of
6,7-Dichloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,3-di-
hydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.(ppm) 7.85 (s, 1H),
7.33 (m, 2H), 7.20 (m, 3H), 5.49 (m, 1H), 4.33 (d, 1H), 4.15 (m,
2H), 3.62 (m, 1H), 3.17 (m, 1H), 2.96 (s, 2H), 2.67 (m, 1H), 1.85
(m, 3H), 1.56 (m, 1H), 1.46 (s, 9H), 1.12 (s, 1H). LC/MS
[M+H].sup.+: 547.8
Step-5:
1-(6,7-Dichloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-
-fluoro-benzyl)-piperidine-4-carbonitrile
[0699] Trifluoroacetic acid (0.1 ml, 1.33 mmol) was added to
6,7-Dichloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,3-di-
hydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (70 mg,
0.13 mmol) in DCM at 5-10.degree. C. and the reaction mixture was
stirred for 2-4 h at room temperature. The solution was then
concentrated and neutralised with 1 (N) NaOH solution. The product
was extracted with ethyl acetate and the organic layer was washed
with water and brine solution. The organics were concentrated under
reduced pressure to afford 55 mg (96%) of
1-(6,7-Dichloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fluoro--
benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+: 447.9. `H-NMR
(400 MHz, DMSO-d.sub.6) .delta.(ppm): 7.34 (s, 2H), 7.19 (t, 2H),
6.94 (m, 1H), 6.75 (s, 1H), 5.01 (bs, 1H), 4.37 (bs, 1H), 4.05 (m,
1H), 3.39 (m, 1H), 2.95 (s, 1H), 2.69 (m, 1H), 1.79 (m, 3H), 1.54
(m, 1H), 1.23 (s, 1H). HPLC purity: 95.9%.
Example 60
1-(6-Chloro-7-isopropoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-
-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00087##
[0700] Step 1:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-isopropo-
xy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester
[0701] To a solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-hydroxy--
2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
(150 mg, 0.28 mmol) in acetone was added K.sub.2CO.sub.3 (78 mg,
0.31 mmol) and isopropyl bromide (0.03 ml, 0.57 mmol) at 0.degree.
C. and was refluxed overnight. The reaction mixture was
concentrated, diluted water, extracted with ethyl acetate. The
organic layer was concentrated under reduced pressure and the
residue was purified by flash chromatography (silica-gel, 2%
MeOH-DCM) to afford 155 mg (96.9%) of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-isopropo-
xy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester. LC/MS [M+H].sup.+: 572.2.
Step 2:
1-(6-Chloro-7-isopropoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbo-
nyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0702] Trifluoroacetic acid (0.1 ml, 1.33 mmol) was added to
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-isopropo-
xy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
(155 mg, 0.27 mmol) in DCM at 5-10.degree. C. and the reaction
mixture was stirred for 2-4 h at room temperature. The solution was
then concentrated and neutralised with 1 (N) NaOH solution. The
product was extracted with ethyl acetate and the organic layer was
washed with water and brine solution. The organics were
concentrated under reduced pressure to afford 100 mg (78.5%) of
1-(6-Chloro-7-isopropoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(-
4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
471.8. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.(ppm): 7.34 (bs,
2H), 7.19 (t, 3H), 6.60 (d, 2H), 5.56 (s, 1H), 4.96 (bs, 1H), 4.33
(m, 2H), 4.05 (m, 1H), 3.21 (m, 2H), 2.94 (s, 2H), 2.70 (s, 1H),
1.80 (m, 3H), 1.50 (m, 1H), 1.22 (s, 6H), 0.84 (m, 1H). HPLC
purity: 97.5%.
Example 61
1-(4-Acetyl-6-chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-ca-
rbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00088##
[0703]
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared as
described in example 51.
[0704] To a solution of
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile (70 mg, 0.15 mmol) in
DCM was added triethyl amine (0.02 ml, 0.18 mmol) and acetyl
chloride (0.01 ml, 0.16 mmol) at cold condition. The mixture was
stirred at room temperature for 1 hr, concentrated, diluted with
water and extracted with dichloromethane. The organic layer was
washed with sodium bicarbonate solution followed by water, brine
and dried over Na.sub.2SO.sub.4. Concentration of organic layer
under reduced pressure followed by washing with hexane afforded 50
mg (66.7%) of
1-(4-Acetyl-6-chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-c-
arbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS
[M+H].sup.+: 499.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta.(ppm): 7.33 (m, 2H), 7.19 (m, 2H), 6.67 (m, 1H), 4.33 (m,
1H), 4.02 (m, 1H), 4.02 (m, 1H), 2.93 (m, 3H), 2.68 (s, 6H), 2.32
(bs, 3H), 2.00 (s, 1H), 1.82 (m, 3H), 1.53 (m, 2H), 1.23 (s, 1H),
1.19 (m, 1H), 0.85 (m, 1H). HPLC purity: 92.2%.
Example 62
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-dimeth-
ylamino-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetamide
##STR00089##
[0705]
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared as
described in example 51. Step-1:
{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-dimethy-
lamino-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetic acid methyl
ester
[0706] To a solution of
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile (70 mg, 0.150 mmol)
in DMF was added K.sub.2CO.sub.3 (41.5 mg, 0.30 mmol) and methyl
bromoacetate (0.014 ml, 0.164 mmole) at 0.degree. C. The Reaction
mixture was stirred at room temperature for overnight. The reaction
mixture was diluted with cold water and extracted with ethyl
acetate. The organic layer was concentrated under reduced pressure
to afford 60 mg (75.3%) of
(6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-dimethy-
lamino-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetic acid methyl ester.
LC/MS [M+H].sup.+: 529.2.
Step-2:
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-
-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetamide
[0707] To a solution of
{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-dimethy-
lamino-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetic acid methyl ester
(60 mg, 0.11 mmol) in methanol was saturated with ammonia gas
during 15 minutes at 0.degree. C. The resulting mixture was heated
at 60.degree. C. for 12 hrs. The ammonia solution was concentrated
under reduced pressure. Purification of the crude mass by column
chromatography in 100-200 silica mesh (2%-MeOH-DCM) afforded 40 mg
(68.7%) of
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyp-piperidine-1-carbonyl]-7-dimeth-
ylamino-2,3-dihydrobenzo[1,4]oxazin-4-yl}-acetamide. LC/MS
[M+H].sup.+: 514.3. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta.(ppm): 7.54 (d, 1H), 7.34 (d, 2H), 7.19 (t, 3H), 6.64 (m,
1H), 6.46 (s, 1H), 5.21 (s, 1H), 4.37 (d, 1H), 4.13 (m, 1H), 3.77
(m, 2H), 3.47 (bs, 2H), 2.72 (m, 1H), 2.59 (s, 6H), 2.49 (s, 2H),
1.82 (m, 4H), 1.54 (m, 1H). HPLC purity: 95.8%.
Example 63
1-(6-Chloro-7-dimethylamino-4-methanesulfonyl-3,4-dihydro-2H-benzo[1,4]oxa-
zine-2-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00090##
[0709]
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared as
described in example 51.
[0710] To a solution of
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile (50 mg,0.10 mmol) in
DCM was added triethylamine (0.05 ml, 0.36 m.mol) and methane
sulfonyl chloride (0.009 ml, 0.12 mmol) in cold condition. The
reaction mixture was stirred at room temperature for 1 hr. The
reaction mixture was concentrated, diluted with water and extracted
with dichloromethane. The organic layer was washed with bicarbonate
solution, water, brine and dried over Na.sub.2SO.sub.4.
Concentration of organic layer under reduced pressure followed by
washing with hexane afforded 35 mg (59.7%)
1-(6-Chloro-7-dimethylamino-4-methanesulfonyl-3,4-dihydro-2H-benzo[1,4]ox-
azine-2-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile.
LC/MS [M+H].sup.+: 535.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta.(ppm): 7.56 (bs, 1H), 7.36 (m, 2H), 5.19 (m, 1H), 4.42 (m,
1H), 3.58 (m, 1H), 3.35 (m, 1H), 3.25 (d, 3H), 3.17 (m, 1H), 3.03
(m, 1H), 2.92 (bs, 1H), 2.77 (s, 6H), 2.33 (s, 3H), 2.08 (s, 1H),
1.80 (m, 3H). HPLC purity: 93.5%
Example 64
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-isopro-
poxy-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetamide
##STR00091##
[0711] Step 1:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-isopropo-
xy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester
[0712] To a solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-hydroxy--
2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
(150 mg, 0.28 mmol in acetone was added K.sub.2CO.sub.3 (78 mg,
0.31 mmol) and isopropyl bromide (0.03 ml, 0.57 mmol) at 0.degree.
C. and was refluxed overnight. The reaction mixture was
concentrated, diluted water, extracted with ethyl acetate. The
organic layer was concentrated under reduced pressure and the
residue was purified by flash chromatography (silica-gel, 2%
MeOH-DCM) to afford 155 mg (96.9%)of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-isopropo-
xy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester. LC/MS [M+H].sup.+: 572.2.
Step 2:
1-(6-Chloro-7-isopropoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbo-
nyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0713] Trifluoroacetic acid (0.1 ml, 1.33 mmol) was added to
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-isopropo-
xy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
(155 mg, 0.27 mmol) in DCM at 5-10.degree. C. and the reaction
mixture was stirred for 2-4 h at room temperature. The solution was
then concentrated and neutralised with 1 (N) NaOH solution. The
product was extracted with ethyl acetate and the organic layer was
washed with water and brine solution. The organics were
concentrated under reduced pressure to afford 100 mg (78.5%) of
1-(6-Chloro-7-isopropoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(-
4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
471.8.
Step 3:
(6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-
-isopropoxy-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetic acid methyl
ester
[0714] To a solution of
1-(6-Chloro-7-isopropoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(-
4-fluoro-benzyl)-piperidine-4-carbonitrile (70 mg, 0.15 mmol) in
DMF was added methyl bromoacetate (0.12 ml,1.31 mmol) and stirred
the reaction mixture for overnight. The reaction mixture was heated
for 2 hour. The reaction mixture was diluted with ice-water and
extracted with ethyl acetate. The organic layer was concentrated
under reduced pressure and the residue was purified by flash
chromatography (silica-gel, 20% ethyl acetate-hexane) to afford 70
mg (85.7%)
{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-isoprop-
oxy-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetic acid methyl ester.
LC/MS [M+H].sup.+:544.0.
Step 4:
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-
-7-isopropoxy-2,3- dihydro-benzo[1,4]oxazin-4-yl}-acetamide
[0715] A solution of
{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-isoprop-
oxy-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetic acid methyl ester (60
mg, 0.11 mmol) in methanol was saturated with ammonia by purging
with ammonia gas at atmospheric pressure at -5.degree. C. The
resulting mixture was heated overnight at 60.degree. C. in a sealed
tube. The mixture was then concentrated and washed with hexane to
afford 18 mg (30.9%)
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-isopr-
opoxy-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetamide. LC/MS
[M+H].sup.+: 529.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta.(ppm): 7.36 (m,2H), 7.24 (m,1H), 7.15 (m,2H), 6.99 (m,1H),
6.55 (m,2H), 5.40 (bs, 1H) 4.38 (m, 1H), 4.26 (m, 1H), 3.81 (s,
1H), 3.48 (m, 2H), 2.96 (s, 2H), 1.88 (m, 2H), 1.66 (m, 2H), 1.54
(m, 1H), 1.36 (m, 2H), 1.24 (s, 6H), 0.87(m,1H). HPLC purity:
93.1%
Example 65
2-[6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-ethoxy-
-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetamide
##STR00092##
[0716]
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-hy-
droxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester was prepared by a process as described in example 37. Step-1:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-ethoxy-2-
,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
[0717] To a solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-hydroxy--
2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
(500 mg, 0.9433 mmol) in acetone was added K.sub.2CO.sub.3 (260.7
mg, 1.88 mmol) and ethyl Iodide (0.22 ml, 2.83 mmol) in cold
condition. The reaction mixture was allowed to reflux for 5 hrs.
Then reaction mixture was concentrated and the crude was diluted
with water, extracted with ethyl acetate. The organic layer was
washed with water and brine and dried over Na.sub.2SO.sub.4. The
organics was concentrated under reduced pressure and purified over
column chromatography (Si-gel, 20% ethyl acetate-hexane) to afford
430 mg (81.7%) of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-ethoxy-2-
,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester.
LC/MS [M+H].sup.+: 558.0
Step-2:
1-(6-Chloro-7-ethoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-
-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0718] To a solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-ethoxy-2-
,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
(430 mg,0.77 mmol) in DCM was added trifluoroacetic acid (0.4
ml,6.16 mmol) drop wise in cold condition. The reaction mixture was
allowed to stir at room temperature for one and half an hour. The
reaction mixture was concentrated, diluted with water, basified
with 2N NaOH solution and extracted with ethyl acetate. The organic
layer was washed with water, brine and dried over Na.sub.2SO.sub.4.
Concentration of the organic extract under vacuum followed by
washing with hexane afforded 300 mg (85.2%) of compound
1-(6-Chloro-7-ethoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
458.3.
Step-3:
(6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-
-ethoxy-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetic acid methyl
ester
[0719] To a solution of
1-(6-Chloro-7-ethoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile (100 mg, 0.22 mmol) in DMF
was added K.sub.2CO.sub.3 (61.4 mg, 0.43 mmol) and methyl
bromoacetate (0.02 ml, 0.24 mmol) at 0.degree. C. The reaction
mixture was stirred for overnight at room temperature. The reaction
mixture was diluted with water and extracted with ethyl acetate.
The organic layer was concentrated under reduce pressure to afford
90 mg (78.2%) of
{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-ethoxy--
2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetic acid methyl ester. LC/MS
[M+H].sup.+: 530.3
Step-4:
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-
-7-ethoxy-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetamide
[0720] To a solution of
{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-ethoxy--
2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetic acid methyl ester (90 mg,
0.16 mmol) in methanol, was saturated with ammonia gas during 15
minutes at 0.degree. C. The resulting mixture was heated at
60.degree. C. for 12 hrs in a sealed tube. Then reaction mass was
concentrated under reduced pressure and purified over Si-gel column
(2-2.5% MeOH-DCM) to afford 60 mg (68.6%) of
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyp-piperidine-1-carbonyl]-7-ethoxy-
-2,3-dihydro-benzo[1,4]oxazin-4-yl]-acetamide. LC/MS [M+H].sup.+:
515.0. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.(ppm): 7.50 (m,
1H), 7.35 (bs, 2H), 7.19 (t, 3H), 6.62 (m, 1H), 6.49 (bs, 1H), 5.22
(s, 1H), 4.20 (m, 1H), 4.10 (m, 1H), 3.96 (m, 2H), 3.75 (m, 2H),
3.45 (s, 2H), 2.94 (bs, 2H), 2.84 (m, 1H). HPLC purity: 96.6%.
Example 66
1-(6-Chloro-7-ethoxy-4-methanesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazine-2--
carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00093##
[0722]
1-(6-Chloro-7-ethoxy-4-methanesulfonyl-3,4-dihydro-2H-benzo[1,4]oxa-
zine-2-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was
prepared from
1-(6-Chloro-7-ethoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile by a similar process as
described in example 46. LC/MS [M+H].sup.+: 536.3. `H-NMR (400 MHz,
DMSO-d.sub.6) .delta.(ppm): 7.56-6.48 (m, 6 Ar H), 4.65 (br s, 1H),
4.11-3.44 (m, 4H), 3.06 (s, 3H0, 2.93-2.87 (m, 3H), 1.96 (m, 2H),
1.64-1.42 (m, 5H). HPLC purity: 98.3%.
Example 67
1-(6-Chloro-7-pyrrolidin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-
-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00094##
[0723]
1-(7-Bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4--
(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared by a
process described in example 57. Step-1:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-pyrrolid-
in-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester
[0724] To a solution of
1-(7-Bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-flu-
oro-benzyl)-piperidine-4-carbonitrile (150 mg, 0.25 mmol) in
toluene was added pyrolidine (18 mg, 0.25 mmol) and cesium
carbonate (248 mg, 0.75 mmol). The solution was degassed with argon
during 1 hour. To the previous degassed solution was added
Pd.sub.2(dba).sub.3 (15 mg, 0.02 mmol) followed by BINAP (32 mg,
0.04 mmol) and was heated at 100 C overnight. The reaction mixture
was passed through a celite bed was diluted with water. The
organics was extracted with ethyl acetate. The organic layer was
concentrated and purified over Si-gel (15% EtOAc-Hex)) to afford 80
mg (54.4%) of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-pyrrolid-
in-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester. LC/MS [M+H].sup.+: 583.4
Step-2:
1-(6-Chloro-7-pyrrolidin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2--
carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0725] To a solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-pyrrolid-
in-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester (80 mg, 0.14 mmol) in dichloromethane was added
trifluoroacetic acid (0.3 ml). The reaction mixture was stirred for
3 hours and concentrated. The organics was diluted with water,
basified with 10% aqueous sodium hydroxide solution and extracted
with ethyl acetate. The organic layer was dried over sodium sulfate
and concentrated to afford 40 mg (60.6%) of
1-(6-Chloro-7-pyrrolidin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl-
)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
483.4. `H-NMR (400 MHz, DMSO-d.sub.6) .delta.(ppm): 7.06 (m, 4H),
6.69 (bs, 1H), 6.48 (m, 2H), 4.77 (m, 2H), 4.64 (m, 2H), 4.25 (m,
2H), 3.44 (m, 2H), 3.36-2.92 (m, 11H), 2.85 (s, 2H), HPLC purity:
94.1%.
Example 68
1-(7-Azetidin-1-yl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00095##
[0726]
1-(7-Bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4--
(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared by a
process described in example 57.
[0727]
1-(7-Azetidin-1-yl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared by
a similar process as described in CF00416. LC/MS [M+H].sup.+:
469.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.(ppm): 7.46 (m,
2H), 7.21 (m, 2H), 6.57 (s, 1H), 6.09 (m, 1H), 5.43 (s, 1H), 4.91
(bs, 1H), 4.07 (bs, 1H), 4.02 (bs, 1H), 3.76 (s, 4H), 3.18 (m, 2H),
2.95 (bs, 2H), 2.69 (bs, 1H), 2.14 (bs, 2H), 1.79 (m, 4H), 1.69 (m,
1H). HPLC purity: 83.91%.
Example 69
1-(6-Chloro-7-difluoromethoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-
-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00096##
[0728]
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-hy-
droxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester was prepared by a process as described in example 37. Step-1:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-difluoro-
methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester
[0729] To a solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-hydroxy--
2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
(200 mg, 0.38 mmol) in THF was added KOtBu (47 mg, 0.43 mmol) at
0.degree. C. and stirred the reaction mixture for one hour. The
reaction mixture was cooled to -78.degree. C. and condensed CHF2Cl
until its volume became double to that initial. The reaction
mixture was stirred at room temperature with Dewar condenser at
room temperature for 5 hours. The reaction mixture was
concentrated, diluted with ice-water, extracted with ethyl acetate.
The organic layer was concentrated under reduced pressure and the
residue was purified by flash chromatography (silica-gel, 15% ethyl
acetate-hexane) to afford 80 mg (36.8%) of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-difluoro-
methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester. LC/MS [M+H].sup.+: 580.4. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.(ppm): 7.77 (m, 1H) 7.33 (m, 2H), 7.22 (m,
3H), 6.96 (d, 1H), 4.34 (d, 1H), 4.23 (d, 1H), 3.39 (d, 1H), 3.17
(m, 1H), 2.95 (m, 2H), 2.66 (m, 1H), 1.85 (m, 3H) 1.79 (m, 1H),
1.53 (m, 1H), 1.43 (s, 9H), 1.24 (m, 1H).
Step-2
1-(6-Chloro-7-difluoromethoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-
-4-(4-fluoro- benzyl)-piperidine-4-carbonitrile
[0730] Trifluoroacetic acid (0.1 ml, 1.33 mmol) was added of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-difluoro-
methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester (80 mg, 0.14 mmol) in DCM at 5-10.degree. C. and the reaction
mixture was stirred for 2-4 h at room temperature. The solution was
then concentrated and neutralised with 1 (N) NaOH solution. The
product was extracted with ethyl acetate and the organic layer was
washed with water and brine solution. The organics were
concentrated under reduced pressure to afford 53 mg (84.9%) of
1-(6-Chloro-7-difluoromethoxy-3,4-dihydro-2H-1-benzo[1,4]oxazine-2-carbon-
yl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS
[M+H].sup.+: 480.0. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta.(ppm): 7.34 (bs, 2H), 7.19 (t, 2H), 6.81 (m, 1H), 6.69 (s,
1H), 6.15 (s, 11-1), 5.04 (m, 1H), 4.37 (m, 1H), 4.05 (m,1H), 3.40
(m, 1H), 3.31 (m, 1H), 3.15 (m, 1H), 2.94 (s, 2H), 2.72 (m, 1H),
1.98 (s, 3H), 1.72 (m, 1H), 1.24 (m, 1H). HPLC: 94.1%.
Example 70
1-(7-Chloro-6-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile
##STR00097## ##STR00098##
[0731]
7-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-6-hy-
droxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester was prepared by a process similar to that described in
example 37. LC/MS [M+H].sup.+: 530.6. Step-9:
7-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-6-methoxy--
2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tent-butyl
ester
[0732] Anhydrous K.sub.2CO.sub.3 (30.4 mg, 0.22 mmol) and methyl
iodide (0.02 ml, 0.34 mmol) were added to
7-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-6-hydroxy--
2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
(60 mg, 0.11 mmol) in acetone and the resulting mixture was stirred
at 50.degree. C. overnight. The mixture was then diluted with
crushed ice and extracted with ethyl acetate. The organic layer was
concentrated and purified through column chromatography over Si-gel
(20% ethyl acetate-hexane) to afford 10 mg (2%) of
7-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-6-methoxy--
2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester.
LC/MS [M+H].sup.+: 544.6.
Step-10:
1-(7-Chloro-6-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbony-
l)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0733] To a solution of
7-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-6-methoxy--
2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
(10 mg, 0.02 mmol)) in DCM was added trifluoroacetic acid (0.1 ml).
The reaction mixture was stirred for about 5 h then concentrated
and washed with dry ether. The resulting TFA salt was diluted with
a minimum volume of water and neutralized with aq. NaOH solution at
5-10.degree. C. Extraction of the neutralized solution with ethyl
acetate followed by concentration afforded 6 mg (75%) of
1-(7-Chloro-6-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-f-
luoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+: 444.3.
HPLC: 87%.
Example 71
1-(6-Chloro-7-diethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4--
(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00099##
[0734]
7-Amino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester was prepared by a process as
described in example 51. Step-1:
6-Chloro-7-diethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester
[0735] To a solution of
7-Amino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester (500 mg, 1.40 mmol) in DMF
was added K.sub.2CO.sub.3 (774.6 mg, 5.60 mmol) and ethyl Iodide
(0.56 ml, 7.00 mmol) in cold condition. The reaction mixture was
allowed to reflux for 10 hrs. The reaction mass was diluted with
water and extracted with ethyl acetate. The organic layer was
washed with water, brine and dried over Na.sub.2SO.sub.4. The
organics was concentrated under reduced pressure followed by
washing with hexane to afford 500 mg (86.5%) of
6-Chloro-7-diethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester. LC/MS [M+H].sup.+:
413.0.
Step-2:
6-Chloro-7-diethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarbo-
xylic acid 4-tert-butyl ester
[0736] To a solution of
6-Chloro-7-diethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester (500 mg, 0.35 mmol) in
THF-water (3:1) was added LiOH.H.sub.2O (55.8 mg, 1.33 mmol) in
cold condition. The mixture was allowed to stir at room temperature
for one and half an hour. Then THF was evaporated and the rest mass
was diluted with water, neutralized with AcOH and extracted with
ethyl acetate. Ethyl acetate extract was washed with water, brine.
The organic layer was dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure followed by washing of crude mass with
hexane to afford 350 mg (75.2%) of
6-Chloro-7-diethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester. LC/MS [M+H].sup..+-.: 384.9.
Step-3:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7--
diethylamino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester
[0737] To a solution of
6-Chloro-7-diethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (350 mg, 0.91 mmol) in DMF was added EDCI
(226.6 mg, 1.18 mmol), HOBT (61.4 mg, 0.45 mmol) and DIPEA (0.5 ml,
2.72 mmol) at 0.degree. C. The resulting mixture was allowed to
stir at room temperature for 30 minutes. Then a solution of
4-(4-Fluoro-benzyl)-piperidine-4-carbonitrile in DMF was added to
it at 5.degree. C. and the reaction mixture was allowed to stir at
room temperature for overnight. The reaction mass was diluted with
ice water, stirred for 10 minutes and extracted with ethyl acetate.
Ethyl acetate layer was washed with water and brine, then dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
crude mass was purified over Si gel column (0.5%MeOH-DCM) to afford
350 mg (65.7%) of compound
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-diethyla-
mino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester. LC/MS [M+H].sup.+: 585.3.
Step-4:
1-(6-Chloro-7-diethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-car-
bonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0738] To a solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-diethyla-
mino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester (350 mg,0.59 mmol) in DCM was added trifluoroacetic acid
(0.36 ml,4.78 mmol) drop wise in cold condition. The reaction
mixture was allowed to stir at room temperature for 3 hours. Then
DCM was concentrated. The crude mass was diluted with water,
basified with 2N NaOH solution and extracted with ethyl acetate.
The organic layer was concentrated under reduced pressure to afford
250 mg (86.2%) of
1-(6-Chloro-7-diethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile.
[0739] LC/MS [M+H].sup.+: 485.2. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 7.73 (s, 2H), 7.19 (t, 2H), 6.59 (d,
2H), 5.85 (s, 1H), 4.97 (s, 1H), 4.38 (d, 1H), 4.09 (m, 1H), 3.15
(m, 2H), 2.94 (s, 2H), 2.89 (s, 4H), 2.71 (d, 1H), 1.98 (m, 4H),
1.72 (bs, 1H), 0.98 (s, 6H). HPLC: 96.3%.
Example 72
1-(6-Chloro-7-morpholin-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00100##
[0740]
1-(6-Chloro-7-morpholin-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-car-
bonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared
by a similar process as described in example 67. LC/MS [M+H].sup.+:
498.9. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.34 (bs,
2H), 7.19 (m, 2H), 6.64 (m, 1H), 6.54 (m, 1H), 5.81 (s, 1H), 4.96
(m, 1H), 4.41 (m, 1H), 3.69 (m, 1H), 3.36 (bs, 4H), 3.22 (m, 1H),
3.15 (m, 2H), 2.95 (bs, 2H0, 2.80 (m, 4H), 1.98-1.73 (m, 5H). HPLC:
96.4%
Example 73
(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-phe-
noxy)-piperidin-1-yl]-methanone
##STR00101##
[0741] 4-(4-Floro-phenoxy)-piperidine was prepared by a process
similar to that described in example 64.
7-Benzyloxy-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester was prepared by a process similar to that
described in example 37 of priority application. Step-1:
7-Benzyloxy-6-chloro-2-[4-(4-fluoro-phenoxy)-piperidine-1-carbonyl]-2,3-d-
ihydro-benzo[1,4]oxazine-4-carboxylic acid tent-butyl ester
[0742] To a solution of
7-Benzyloxy-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (250 mg, 0.59 mmol) in DMF was added
4-(4-Floro-phenoxy)-piperidine (115.2 mg, 0.59 mmol), EDCI (147.6
mg, 0.77 mmol), HOBt (39.2 mg, 0.3 mmol) and DIPEA (0.5 ml, 2.95
mmol) at 5-10.degree. C. The reaction mixture was stirred at room
temperature for 15 hours then diluted with water and extracted with
ethyl acetate. The ethyl acetate layer was concentrated in vacuo
and subjected to column chromatography (Si-gel, 15% EtOAc-hexane)
to afford 50 mg (14.2%) of
7-Benzyloxy-6-chloro-2-[4-(4-fluoro-phenoxy)-piperidine-1-carbonyl]-2,3-d-
ihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester. LC/MS
[M+H].sup.+: 597.4.
Step-2:
6-Chloro-2-[4-(4-fluoro-phenoxy)-piperidine-1-carbonyl]-7-hydroxy-
-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester
[0743]
7-Benzyloxy-6-chloro-2-[4-(4-fluoro-phenoxy)-piperidine-1-carbonyl]-
-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
(140 mg, 0.23 mmol) dissolved in ethyl acetate was hydrogenated
with 5% Pd--C (50 mg) for 4 hour. The catalyst was removed by
filtration through a celite bed. Concentration of the organics
afforded 110 mg (94.3%) of
6-Chloro-2-[4-(4-fluoro-phenoxy)-piperidine-1-carbonyl]-7-hydroxy-2,3-dih-
ydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester. LC/MS
[M+H].sup.+: 507.1.
Step-3:
6-Chloro-2-[4-(4-fluoro-phenoxy)-piperidine-1-carbonyl]-7-methoxy-
-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tent-butyl
ester
[0744] To a solution of
6-Chloro-2-[4-(4-fluoro-phenoxy)-piperidine-1-carbonyl]-7-hydroxy-2,3-dih-
ydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (110 mg,
0.22 mmol) in acetone was added K.sub.2CO.sub.3 (60 mg, 0.43 mmol)
and methyl iodide (0.04 ml, o.65 mmol). The reaction mixture was
refluxed overnight and was filtered. The organics was concentrated
and purified over Si-gel (20% EtOAc-hexane) to afford 110 mg
(95.9%) of
6-Chloro-2-[4-(4-fluoro-phenoxy)-piperidine-1-carbonyl]-7-methoxy-2,3-dih-
ydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester. LC/MS
[M+H].sup.+: 521.6
Step-4:
(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-f-
luoro-phenoxy)-piperidin-1-yl]-methanone
[0745] Trifluoroacetic acid (0.2 ml, 2.11 mmol) was added of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-difluoro-
methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester (110 mg,0.211 mmol) in DCM at 5-10.degree. C. and the
reaction mixture was stirred for 2-4 h at room temperature. The
solution was then concentrated and neutralised with 1 (N) NaOH
solution. The product was extracted with ethyl acetate and the
organic layer was washed with water and brine solution. The
organics were concentrated under reduced pressure to afford 50 mg
(56.5%) of
1-(6-Chloro-7-difluoromethoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl-
)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
421.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.12 (t,
2H), 7.02 (m, 2H), 6.64 (s, H), 6.58 (bs, H), 5.59 (s, H), 4.96 (s,
H), 4.59 (bs, H), 3.82 (m, 2H), 3.47 (s, 3H), 3.33 (m, 2H), 3.21
(m, 2H), 1.98 (m, 3H). HPLC: 93.8%.
Example 74
1-[6-Chloro-4-(2-hydroxy-ethyl)-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-
-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00102##
[0746]
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared by a
process as described in example 27.
[0747] To a solution of
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-f-
luoro-benzyl)-piperidine-4-carbonitrile (100 mg,0.23 mmol) in DMF
was added bromoethanol (0.017 ml,0.25 mmol) and
K.sub.2CO.sub.3(63.5 mg, 0.46 mmol). The reaction mixture was
warmed at 60.degree. C. overnight. The reaction mixture was diluted
with water and extracted with ethyl acetate. The organic layer was
washed with water and concentrated under reduced pressure to afford
70 mg (62.4%) of
1-[6-Chloro-4-(2-hydroxy-ethyl)-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-
e-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS
[M+H].sup.+: 488.6. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.25-6.48 (m, 6Ar--H), 4.91-4.33 (m, 3H), 3.84-2.8 (m, 14H),
1.89 (m, 2H), 1.41-1.24 (m, 2H). HPLC: 93.4%.
Example 75
1-[6-Chloro-7-dimethylamino-4-(2-hydroxy-ethyl)-3,4-dihydro-2H-benzo[1,4]o-
xazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00103##
[0748]
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared as
described in example 51.
[0749] To a solution of
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile (100 mg, 0.21 mmol)
in DMF was added K.sub.2CO.sub.3 (60.4 mg, 0.43 mmol) and 2-Bromo
ethanol (0.016 ml, 0.24 mmol). The reaction mixture was heated at
55.degree. C. for 36 hrs. The reaction mass was diluted with water
and extracted with ethyl acetate. The Organic layer was washed with
water, brine and dried over Na.sub.2SO.sub.4. The organics was
concentrated under reduced pressure and purified through Si-gel
column (50-55% EtOAc-hexane) to afford 40 mg (36.6%) of
1-[6-Chloro-7-dimethylamino-4-(2-hydroxy-ethyl)-3,4-dihydro-2H-benzo[1,4]-
oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile.
LC/MS [M+H].sup.+:501.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 7.34 (bs, 2H), 7.19 (t, 2H), 6.72 (s, 1H), 6.62(m,
1H), 4.99 (s, 1H), 4.70 (bs, 1H), 4.40 (m, 1H), 4.10 (m, 1H), 3.55
(bs, 2H), 3.46 (s, 2H), 3.32 (m, 2H), 3.25 (m, 1H), 2.93 (d, 2H),
2.67 (s, 1H), 2.58 (bs, 6H), 1.79(m, 3H), 1.53(m, 1H). HPLC:
95.6%
Example 76
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-dimethyla-
mino-2,3-dihydro-benzo[1,4]oxazine-4-carbonitrile
##STR00104##
##STR00105##
[0750]
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared as
described in example 51.
[0751] To a solution of
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile (100 mg, 0.22 mmol)
in DMF was added K.sub.2CO.sub.3 (60 mg, 0.44 mmol) and cyanogen
bromide (28 mg, 0.26 mmol) at cold condition. The reaction mixture
was stirred for overnight. The reaction mixture was diluted with
water and extracted with ethyl acetate. The organic layer was
concentrated under reduced pressure and the residue was purified by
flash chromatography (silica-gel, 2% MeOH-DCM) to afford 50 mg
(48%) of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-dimethyl-
amino-2,3-dihydro-benzo[1,4]oxazine-4-carbonitrile. LC/MS
[M+H].sup.+:482.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm):7.34(d, 2H, J=5.88), 7.19(t, 2H), 6.98(brs, 1H), 6.78(m, 1H),
4.38(m, 1H), 4.36(m, 1H), 4.16(m, 2H), 3.91(m,2H), 2.94(s, 2H),
2.67(m, 6H), 1.90 to 0.95(5H).
[0752] HPLC: 87.7%.
Example 77
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(6-fluoro-pyridin-3-ylmethyl)-piperidine-4-carbonitrile
##STR00106##
##STR00107##
[0753] Step-1: 5-Bromomethyl-2-fluoro-pyridine
[0754] To a solution of 2-Fluoro-5-methyl-pyridine (500 mg, 4.5
mmol) in 10 ml of CCl.sub.4 NBS (800 mg, 4.5 mmol) and benzoyl
peroxide (25 mg) was added in cold condition. The resulting mixture
was allowed to stir at room temperature for 30 minutes and then
refluxed for one hour.
[0755] The reaction mixture was cooled and diluted with water. The
organic layer was separated and washed with sodium bicarbonate
solution followed by water and brine, then dried over
Na.sub.2SO.sub.4 and concentrated under vacuum. The crud mass was
purified by column chromatography (Si-gel, 5% ethyl acetate) to
afford 350 mg (41%) of 5-Bromomethyl-2-fluoro-pyridine.GCMS (M/z):
189. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 8.34 (s,
H), 8.04 (m, H), 7.21 (dd, 1H), 4.76 (s, 2H).
Step-2:
4-Cyano-4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-1-carboxylic
acid tert-butyl ester
[0756] To a solution of of DIPEA (0.3 ml, 2.21 mmol) in dry THF,
was added n-BuLi (2.58 mmol) solution dropwise at 0.degree. C. The
mixture was allowed to stir for 1 hr at room temperature. To this
mixture a solution of N-boc-4-cyanopipyridine (387 mg, 1.84 mmol)
in dry THF was added dropwise at -78.degree. C. The resulting
mixture was allowed to stir for two hours at -78.degree. C. to
0.degree. C. Then a solution of 5-Bromomethyl-2-fluoro-pyridine
(350 mg, 1.84 mmol) in dry THF was added dropwise at -78.degree. C.
and the resulting mixture was allowed to stir at room temperature
overnight. The reaction was quenched with saturated NH.sub.4Cl
solution in cold condition and stirred at room temperature for 30
minutes. THF layer was separated and the aqueous layer was
extracted with ethyl acetate. The combined organic layers (THF and
ethyl acetate) was washed with water and brine, then dried over
Na.sub.2SO.sub.4 and concentrated under vacuum. The crud mass was
purified by column chromatography (Si-gel, 12% ethyl
acetate-hexane) to afford 400 mg (68%) of
4-Cyano-4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-1-carboxylic
acid tert-butyl ester. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm):8.16 (s, H), 7.92 (t, 1H, J=8.24 Hz), 7.20 (d, H, J=8.36 Hz),
4.01 (d, 2H, J=13.36 Hz), 2.98 (s, 2H), 2.81(bs, 2H), 1.76 (d, 2H,
J=13.28 Hz), 1.56 (m, 2H), 1.39 (s, 9H). LCMS
[M+H].sup.+:320.2.
Step 3:
4-(6-Fluoro-pyridin-3-ylmethyl)-piperidine-4-carbonitrile
[0757] To a solution of
4-Cyano-4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-1-carboxylic
acid tert-butyl ester (400 mg, 1.25 mmol) in DCM was added
trifluoroacetic acid (0.97 ml, 12.52 mmol) dropwise in cold
condition. The mixture was allowed to stir at room temperature for
one and half an hour. Then DCM was evaporated and the crude mass
was diluted with water, basified with 2N NaOH solution and
extracted with ethyl acetate. Ethyl acetate extract was washed with
water and brine, then dried over Na.sub.2SO.sub.4. The organic
layer was concentrated under vacuum to afforde 230 mg (84%) of
4-(6-Fluoro-pyridin-3-ylmethyl)-piperidine-4-carbonitrile.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 8.14 (s, H),
7.91 (t, H, J=8.2 Hz), 7.19 (d, H, J=8.36 Hz), 2.93 (s, 4H), 2.56
(m, 2H), 1.66 (d, 2H, J=12.6 Hz), 1.48 (m, 2H). LCMS [M+H].sup.+:
220.2.
Step-4:
6-Chloro-2-[4-cyano-4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-1--
carbonyl]-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tent-butyl ester
[0758] To a solution of
6-Chloro-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (114 mg, 0.32 mmol) in DMF was added
4-(6-Fluoro-pyridin-3-ylmethyl)-piperidine-4-carbonitrile (70 mg,
0.32 mmol), EDCI (183 mg, 0.957 mmol), HOBT (22 mg, 0.16 mmol) and
DIPEA (0.16 ml, 0.957 mmol) at 5-10.degree. C. and the mixture was
stirred at room temperature for 14-16 hours. The reaction mixture
was then diluted with water and extracted with ethyl acetate. The
organic layer was concentrated under reduced pressure and the
residue was purified by flash chromatography (silica-gel, 2%
MeOH-DCM) to afford 105 mg (59%) of
6-Chloro-2-[4-cyano-4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-1-carbonyl-
]-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester. LC/MS [M+H].sup.+: 558.3.
Step-5:
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-ca-
rbonyl)-4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-4-carbonitrile
[0759] Trifluoroacetic acid (0.14 ml, 1.8 mmol) was added to
6-Chloro-2-[4-cyano-4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-1-carbonyl-
]-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester (100 mg, 0.179 mmol) in DCM at 5-10 .degree. C.
and the reaction mixture was stirred for 2-4 h at room temperature.
The solution was then concentrated and neutralised with 2 (N) NaOH
solutions. The product was extracted with ethyl acetate and the
organic layer was washed with water and brine solution. The
organics were concentrated under reduced pressure to afford 50 mg
(61%) of
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-4-carbonitrile. LC/MS
[M+H].sup.+:458.0.
[0760] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 8.71(s,
1H), 7.93 (s, 1H), 7.22 (d, 1H, J=2.16), 6.61 (s, 1H), 6.57 (s,
1H), 5.75 (s, 1H), 4.95 (s, 1H), 4.40 (d, 1H, J=11.44), 4.10 (m,
1H), 3.33-1.39 (16H). HPLC: 98.5%.
Example 78
1-(6-Chloro-7-methylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(-
4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00108##
[0761] Step-1:
7-tert-Butoxycarbonylamino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dic-
arboxylic acid 4-tert-butyl ester 2-methyl ester
[0762] To a solution
7-Amino-6-chloro-2-(1-methoxy-vinyl)-2,3-dihydro-benzo[1,4]oxazine-4-carb-
oxylic acid tert-butyl ester (400 mg, 1.12 mmol) in THF-1,4-dioxane
was added ditertiary butyl dicarbonate (0.3 ml, 1.2 mmol) and DMAP
(14 mg, 0.11 mmol). The reaction mixture was refluxed overnight.
The reaction mixture was concentrated and purified over column
chromatography (Si-gel, 3% ethyl acetate in hexane) to afford 110
mg (21.5%) of
7-tert-Butoxycarbonylamino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dic-
arboxylic acid 4-tert-butyl ester 2-methyl ester. .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. (ppm): 7.83 (s, 1H), 6.83 (s, 1H), 4.70
(m, 1H), 4.35 (d, 1H), 3.60 (d, 1H), 1.50 (s, 3H), 1.43 (m, 2H),
1.45 (s, 9H).
Step-2:
7-tert-Butoxycarbonylamino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-
-2,4-dicarboxylic acid 4-tent-butyl ester
[0763] To a solution
7-tert-Butoxycarbonylamino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dic-
arboxylic acid 4-tert-butyl ester 2-methyl ester (110 mg, 0.24
mmol) in THF-water was added LiOH (15 mg, 0.36 mmol) under ice cold
condition and stirred at room temperature for 2 h. After completion
of the reaction solvent was evaporated, added water, acidified with
50% acetic acid at 0.degree. C. The organics was extracted with
ethyl acetate, washed with water, brine, dried over
Na.sub.2SO.sub.4. The organic layer was concentrated under reduced
pressure to afford 100 mg (97.1%) of
7-tert-Butoxycarbonylamino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dic-
arboxylic acid 4-tert-butyl ester. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 13.3 (bs, 2H), 8.53 (s, 1H), 7.72 (s,
1H), 7.17 (s, 1H), 5.05(s, 1H), 4.40 (d, 1H), 3.57 (d, 1H), 1.42
(s, 18H).
Step-3:
7-tert-Butoxycarbonylamino-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl-
)-piperidine-1-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester
[0764] To a solution of
7-tert-Butoxycarbonylamino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dic-
arboxylic acid 4-tert-butyl ester (0.1 g, 0.23 mmol) in DMF was
added EDCI (0.058 g, 0.30 mmol), HOBT (0.016 g, 0.12 mmol) and
DIPEA (0.1 ml, 0.69 mmol) at 0.degree. C. The reaction mixture was
stirred at room temperature for 1 h and was added
4-(4-Fluoro-benzyl)-piperidine-4-carbonitrile (0.051 g, 0.23 mmol)
at 0.degree. C. The reaction mixture was stirred at room
temperature for overnight. The reaction mixture was diluted with
ice-water and extracted with ethyl acetate. The organic layer was
concentrated to afford 110 mg (73.9%) of
7-tert-Butoxycarbonylamino-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperi-
dine-1-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester. LC/MS [M+H].sup.+:629.3.
Step-4:
7-(tert-Butoxycarbonyl-methyl-amino)-6-chloro-2-[4-cyano-4-(4-flu-
oro-benzyl)-piperidine-1-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxy-
lic acid tert-butyl ester
[0765] To a solution E
7-tert-Butoxycarbonylamino-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperi-
dine-1-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester (110 mg, 0.17 mmol) in DMF was added sodium
hydride (10 mg, 0.19 mmol) at 0.degree. C. The reaction mixture was
stirred at room temperature for 1 h. Methyl iodide (0.03 ml, 0.53
mmol) was added at 0.degree. C. and the reaction mixture stirred at
room temperature for 2 h. The reaction mixture was diluted with
ice-water and extracted with ethyl acetate. The organic layer was
washed with water and concentrated under reduced pressure. The
crude was purified over column chromatography (Si-gel, 20% ethyl
acetate in hexane) to afford 80 mg (73.2%) of
7-(tert-Butoxycarbonyl-methyl-amino)-6-chloro-2-[4-cyano-4-(4-fluoro-benz-
yl)-piperidine-1-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester. LC/MS [M+H].sup.+: 643.4.
Step-5: 1-(6-Chloro-7-methylamino-3,4-dihydro-2H
benzo[1,4]oxazine-2-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitri-
le
[0766] To a solution of
7-(tert-Butoxycarbonyl-methyl-amino)-6-chloro-2-[4-cyano-4-(4-fluoro-benz-
yl)-piperidine-1-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester (80 mg, 0.12 mmol) in DCM was added
trifluoroacetic acid (1 ml, 12.9 mmol). The reaction mixture was
stirred for about 5 h then concentrated and washed with dry ether.
The resulting TFA salt was diluted with a minimum volume of water
and neutralized with aq. NaOH solution at 5-10.degree. C.
Extraction of the neutralized solution with ethyl acetate followed
by concentration afforded 25 mg (47%) of
1-(6-Chloro-7-methylamino-3,4-dihydro-2H
benzo[1,4]oxazine-2-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitri-
le. LC/MS [M+H].sup.+: 443.1. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 7.34 (bs, 2H), 7.19 (m, 2H), 6.57 (s, 1H), 6.09 (m,
1H), 5.13 (s, 1H), 4.90 (bs, 1H), 4.72 (bs, 1H), 4.40 (d, 1H), 4.09
(m, 1H), 3.15 (m, 2H), 2.95 (bs, 2H), 2.65 (s, 3H), 1.81(m, 2H),
1.54 (m, 1H), 1.39 (m, 2H), 1.14 (s, 1H). HPLC: 98.6%.
Example 79
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-methox-
y-2,3-dihydro-benzo[1,4]oxazin-4-yl}-N-methyl-acetamide
##STR00109##
[0767]
{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-m-
ethoxy-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetic acid ethyl ester
was prepared by a process similar to that described in example
49.
[0768] A solution of
{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-methoxy-
-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetic acid ethyl ester (80 mg,
0.1509 mmol) in ethanol was heated with methylamine solution of
ethanol in sealed tube at 70.degree. C. overnight. The ethanolic
solution was concentrated and purified through column
chromatography (Si-gel, 1.5% MeOH-DCM) to afford 50 mg (64.3%) of
2-{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-metho-
xy-2,3-dihydro-benzo[1,4]oxazin-4-yl}-N-methyl-acetamide. LC/MS
[M+H].sup.+: 515.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.97(m,1H), 7.34(m,2H), 7.19(m,2H), 6.66(m,1H), 6.51(s,1 H),
5.22(brs,1H), 4.39(m,1H), 4.11(m,1H), 3.78-1.53(m,18H). HPLC:
90.9%.
Example 80
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(6-fl-
uoro-pyridin-3-ylmethyl)-piperidine-4-carbonitrile
##STR00110## ##STR00111##
[0769] Step-1: 5-Bromomethyl-2-fluoro-pyridine
[0770] To a solution of 2-Fluoro-5-methyl-pyridine (500 mg, 4.5
mmol) in 10 ml of CCl.sub.4 NBS (800 mg,4.5 mmol) & benzoyl
peroxide (25 mg) was added in cold condition. The resulting mixture
was allowed to stir at room temperature for 30 minutes and then
refluxed for one hour. The reaction mass was cooled and diluted
with water. The organic layer was separated and washed with sodium
bicarbonate solution followed by water and brine, then dried over
Na.sub.2SO.sub.4 and concentrated under vacuum. Purification of the
crude mass over column chromatography (Si-gel, 5% ethyl acetate)
afforded 350 mg (41%) of 5-Bromomethyl-2-fluoro-pyridine. GCMS
(M/z): 189. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 8.34
(s, H), 8.04 (m, H), 7.21 (dd, H, J=2.6 Hz), 4.76 (s,2H).
Step-2:
4-Cyano-4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-1-carboxylic
acid tert-butyl ester
[0771] To a solution of of DIPEA (0.3 ml, 2.21 mmol) in dry THF,
was added n-BuLi (2.58 mmol) solution dropwise at 0.degree. C. The
mixture was allowed to stir for 1 hr at room temperature. To this
mixture a solution of N-boc-4-cyanopipyridine (387 mg, 1.84 mmol)
in dry THF was added dropwise at -78.degree. C. The resulting
mixture was allowed to stir for two hours at -78.degree. C. to
0.degree. C. Then a solution of 5-Bromomethyl-2-fluoro-pyridine
(350 mg, 1.84 mmol) in dry THF was added dropwise at -78.degree. C.
and the resulting mixture was allowed to stir at room temperature
overnight. The reaction was quenched with saturated NH.sub.4Cl
solution in cold condition and stirred at room temperature for 30
minutes. THF layer was separated and the aqueous layer was
extracted with ethyl acetate. The combined organic layers (THF and
ethyl acetate) was washed with water and brine, then dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Purification of the crude by column chromatography over silica gel
(12% ethyl acetate-hexane) afforded 400 mg (68%) of
4-Cyano-4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-1-carboxylic
acid tert-butyl ester. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 8.16 (s, H), 7.92 (t, H, J=8.24Hz), 7.20 (d, H, J=8.36 Hz),
4.01 (d, 2H, J=13.36 Hz), 2.98 (s, 2H), 2.81(bs, 2H), 1.76 (d, 2H,
J=13.28 Hz), 1.56 (m, 2H), 1.39 (s, 9H). LCMS
[M+H].sup.+:320.2.
Step 3:
4-(6-Fluoro-pyridin-3-ylmethyl)-piperidine-4-carbonitrile
[0772] To a solution of
4-Cyano-4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-1-carboxylic
acid tert-butyl ester (400 mg, 1.25 mmol) in DCM was added
trifluoroacetic acid (0.97 ml, 12.52 mmol) dropwise in cold
condition. The mixture was allowed to stir at room temperature for
one and half hour. The reaction mixture was evaporated and the
crude mass was diluted with water, basified with 2N NaOH solution
and extracted with ethyl acetate. The organic layer was washed with
water and brine, then dried over Na.sub.2SO.sub.4. The organic
layer was concentrated under reduced pressure to afford 230 mg
(84%) of 4-(6-Fluoro-pyridin-3-ylmethyl)-piperidine-4-carbonitrile.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 8.14 (s, H),
7.91 (t, H, J=8.2 Hz), 7.19 (d, H, J=8.36 Hz), 2.93 (s, 4H), 2.56
(m, 2H), 1.66 (d, 2H, J=12.6 Hz), 1.48 (m, 2H). LCMS [M+H].sup.+:
220.2.
Step-4:
7-Benzyloxy-6-chloro-2-[4-cyano-4-(6-fluoro-pyridin-3-ylmethyl)-p-
iperidine-1-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester
[0773] To a solution of
7-Benzyloxy-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (440 mg, 1.05 mmol) in 1.5 ml of DMF was
added EDCI (261.4 mg, 1.36 mmol), HOBT (71 mg, 0.52 mmol) and DIPEA
(0.54 ml 3.14 mmol) at 10.degree. C. The resulting reaction mixture
was allowed to stir at room temperature for 30 minutes. Then a
solution of
4-(6-Fluoro-pyridin-3-ylmethyl)-piperidine-4-carbonitrile in DMF
(0.5 ml) was added to it at 10.degree. C. and the reaction mixture
was allowed to stir at room temperature overnight. The reaction
mass was diluted with ice-water, stirred for 10 minutes and
extracted with ethyl acetate. The organic layer was washed with
water and brine, then dried over Na.sub.2SO.sub.4 and concentrated
under vacuum. Purification of the crude organic mass by column
chromatography (Si-gel, 0.2%MeOH-DCM) afforded 300 mg (46%) of
7-Benzyloxy-6-chloro-2-[4-cyano-4-(6-fluoro-pyridin-3-ylmethyl)-piperidin-
e-1-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 8.16 (d, H, J=15.76 Hz), 7.91 (m, H), 7.44 (m, 3H), 7.34 (s,
H), 7.21 (d, 2H, J=8.2 Hz), 6.79 (d, H, J=16.08 Hz), 5.47(s, H),
5.16 (s, 2H), 4.34 (bs, H), 4.10 (bs, H), 3.58 (m, H), 3.14 (m, H),
3.02(s, 2H), 2.67(m, H), 1.86 (m, 2H), 1.74 (m, H), 1.56 (m, H),
1.39 (s, 9H), 1.24(s, H), 0.83 (m, H). LCMS [M+H].sup.+: 621.3.
Step-5:
6-Chloro-2-[4-cyano-4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-1--
carbonyl]-7-hydroxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester
[0774]
7-Benzyloxy-6-chloro-2-[4-cyano-4-(6-fluoro-pyridin-3-ylmethyl)-pip-
eridine-1-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester (300 mg, 0.48 mmol) was dissolved in 10 ml of
ethyl acetate and hydrogenated over 5% Pd--C for 5 hrs. Then
reaction mass was filtered through celite bed and the filtrate was
concentrated under vacuum. Purification of the crude over column
chromatography (Si-gel, 1% MeOH-DCM) afforded 200 mg (78%) of
6-Chloro-2-[4-cyano-4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-1-carbonyl-
]-7-hydroxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester. LCMS [M+H].sup.+: 531.4. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 9.9 (bs, H), 8.27 (d, H, J=13.08 Hz),
7.92 (m, H), 7.55 (bs, H), 7.21 (d, H, J=6.6 Hz), 6.49 (d, H,
J=7.36 Hz), 5.35 (d, H, J=26.68), 4.34 (d, H, J=12.56), 4.04 (m,
H), 3.64 (d, H, J=13.26), 3.14 (m, H), 3.02 (s, H), 2.67(m, H),
1.86 (m, 2H), 1.84 (m, 2H), 1.56 (m, H), 1.43 (s, 9H), 1.24 (s,
2H), 0.83 (m, H).
Step-6:
6-Chloro-2-[4-cyano-4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-1--
carbonyl]-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester
[0775] To a solution of
6-Chloro-2-[4-cyano-4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-1-carbonyl-
]-7-hydroxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester (200 mg, 0.377 mmol) in acetone was added
K.sub.2CO.sub.3 (156 mg, 1.13 mmol) and MeI (0.05 ml, 0.75 mmol) at
10.degree. C. The resulting mixture was allowed to reflux for 3 hrs
and concentrated. The crude was diluted with water and extracted
with ethyl acetate. The organic layer was washed with water and
brine, then dried over Na.sub.2SO.sub.4 and concentrated under
vacuum. The crude was washed with hexane to get 195 mg (95%) of
6-Chloro-2-[4-cyano-4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-1-
-carbonyl]-7-methoxy-2,3-dihydro benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 8.16 (d, H, J=14.2 Hz), 7.93 (m, H), 7.65 (bs, H), 7.22 (d,
H, J=10.4 Hz), 6.69 (d, H, J=14.84 Hz), 5.35(d , H, J=26.68), 4.36
(d, H, J=13.6), 4.10 (d, H, J=13.88), 3.81 (s, 3H), 3.61 (d, H,
J=12.6), 3.15 (m, H), 3.02(s, 2H), 2.67 (m, H), 1.89 (m, 3H), 1.52
(m, H), 1.45 (s, 9H), 1.23 (s, 2H), 0.84 (m, H). LCMS [M+H].sup.+:
545.2.
Step-7:
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl-
)-4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-4-carbonitrile
[0776] To a solution of
6-Chloro-2-[4-cyano-4-(6-fluoro-pyridin-3-ylmethyl)-piperidine-1-carbonyl-
]-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester (190 mg, 0.35 mmol) in DCM was added
trifluoroacetic acid (0.3 ml, 3.49 mmol) dropwise in cold
condition. The mixture was allowed to stir at room temperature for
one and half hour. Then DCM was evaporated and the crude mass was
diluted with water, basified with 2N NaOH solution and extracted
with ethyl acetate. The organic layer was washed with water and
brine, then dried over Na.sub.2SO.sub.4. Concentration of the
organic extract under reduced pressure afforded 150 mg (96%) of
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(6-f-
luoro-pyridin-3-ylmethyl)-piperidine-4-carbonitrile. LCMS
[M+H].sup.+: 445.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 8.18 (s, H), 7.94 (s, H), 7.22 (d, H, J=10.48 Hz), 6.62
(m,2H), 5.59(s, H,) 4.98 (d, H, J=13.6), 4.40 (bs, H), 4.04 (m, H),
3.72 (s, 3H), 3.37 (m, H), 3.21(m, 2H), 3.02 (s, 2H), 2.69 (m, H),
1.84 (m, 3H), 1.57 (m, 9H), 1.09 (s, 2H). HPLC: 90%.
Example 81
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-methoxy-2-
,3-dihydro-benzo[1,4]oxazine-4-carbonitrile
##STR00112##
[0777]
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared as
described in example 27.
[0778] To a solution of
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-f-
luoro-benzyl)-piperidine-4-carbonitrile (50 mg, 0.11 mmol), in 1 ml
of DMF was added K.sub.2CO.sub.3 (19 mg, 0.135 mmol) and the
reaction mixture was stirred for half an hour. Then cyanogen
bromide (14.3 mg, 0.135 mmol) was added to the previous reaction
mixture at ice cool condition and the reaction mixture was stirred
for 14 hours. Then the reaction mixture was diluted with water and
extracted with ethyl acetate, washed with brine, dried over sodium
sulfate and evaporated to get the crude mass which was further
purified by column chromatography over silica gel (1.25% methanol
in DCM) to afford 25 mg (47.7%) of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-methoxy--
2,3-dihydro-benzo[1,4]oxazine-4-carbonitile. LC/MS
[M+H].sup.+:469.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.35 (d, 2H), 7.19 (t, 2H), 7.03 (s, 1H), 6.84 (m, 1H), 5.38
(d,1H), 4.37 (d, 1H), 4.13 (m,1H), 3.90 (m, 2H), 3.79 (d, 3H),
3.26-1.39 (m, 8H). HPLC: 91.5%.
Example 82
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carboxylic acid ethyl ester
##STR00113## ##STR00114##
[0779] Step-1: 4-(4-Fluoro-benzyl)-piperidine-1,4-dicarboxylic acid
1-tent-butyl ester 4-ethyl ester
[0780] To a stirred solution of lithium diisopropyl amide in THF
was added Piperidine-1,4-dicarboxylic acid 1-tert-butyl ester
4-ethyl ester (2 g, 7.7 mmol) at -78.degree. C. The reaction
mixture was stirred at -40.degree. C. for 1 hr. Then reaction
mixture was cooled to -78.degree. C. and was added 4-fluorobenzyl
bromide (1.46 g, 7.7 mmole) was added to reaction mass at
-78.degree. C. The resulting mixture was stirred at -78.degree. C.
for 2 hrs. Then reaction mixture was quenched with saturated
ammonium chloride solution and extracted with ethyl acetate.
Organic layer was washed with water and brine, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude
mass was washed with hexane to afford 2.5 g (89.2%) of
4-(4-Fluoro-benzyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl
ester 4-ethyl ester. LC/MS [M+H].sup.+: 366.3.
Step-2: 4-(4-Fluoro-benzyl)-piperidine-4-carboxylic acid ethyl
ester
[0781] To a solution of
4-(4-Fluoro-benzyl)-piperidine-1,4-dicarboxylic acid-1-tert-butyl
ester 4-ethyl ester (1.0 g, 2.7 mmol) in DCM was added
trifluoroacetic acid (2.47 g, 2.18 mmol) drop wise in cold
condition. The reaction mixture was allowed to stir at room
temperature for one and half an hour. The reaction mixture was
evaporated and the crude mass was diluted with water, basified with
2N NaOH solution and extracted with ethyl acetate. The organic
layer was washed with water and then dried over Na.sub.2SO.sub.4.
Concentration of the organic compound under reduced pressure
afforded 700 mg (97.7%) of compound
4-(4-Fluoro-benzyl)-piperidine-4-carboxylic acid ethyl ester. LC/MS
[M+H].sup.+: 266.4.
Step-3:
7-Benzyloxy-6-chloro-2-[4-ethoxycarbonyl-4-(4-fluoro-benzyl)-pipe-
ridine-1-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester
[0782] To a solution of
6-Chloro-7-ethoxy-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (300 mg, 0.71 mmol) in DMF was added EDCI
(178 mg, 0.93 mmol), HOBT (96.5 mg, 0.72 mmol) and DIPEA (276.9 mg,
2.14 mmol) at 10.degree. C. The resulting reaction mixture was
allowed to stir at room temperature for 30 minutes. Then a solution
of 4-(4-Fluoro-benzyl)-piperidine-4-carboxylic acid ethyl ester
(189.5 mg, 0.72 mmol) in DMF was added to it at 10.degree. C. and
the reaction mixture was allowed to stir at room temperature
overnight. The reaction mixture was diluted with ice water, stirred
for 10 minutes and extracted with ethyl acetate. The organic layer
was washed with water, brine and dried over Na.sub.2SO.sub.4. The
organic layer was concentrated under reduced pressure. Purification
of the crude mass by column chromatography (Si-gel, 25%
ethylacetate-hexane) afforded 350 mg (73.4%) of
7-Benzyloxy-6-chloro-2-[4-ethoxycarbonyl-4-(4-fluoro-benzyl)-piperidine-1-
-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester. LC/MS [M+H].sup.+: 667.2.
Step-4:
6-Chloro-2-[4-ethoxycarbonyl-4-(4-fluoro-benzyl)-piperidine-1-car-
bonyl]-7-hydroxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester
[0783] To a solution of
7-Benzyloxy-6-chloro-2-[4-ethoxycarbonyl-4-(4-fluoro-benzyl)-piperidine-1-
-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester (350 mg, 0.52 mmol) in ethyl acetate (20 ml) was
hydrogenated with 5% Pd--C for 3 hours. The reaction mixture was
filtered and concentrated under reduced pressure to afford 300 mg
(99%) of
6-Chloro-2-[4-ethoxycarbonyl-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-
-hydroxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester. LC/MS [M+H].sup.+: 577.4.
Step-5:
6-Chloro-2-[4-ethoxycarbonyl-4-(4-fluoro-benzyl)-piperidine-1-car-
bonyl]-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester
[0784] To a solution of
6-Chloro-2-[4-ethoxycarbonyl-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-
-hydroxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester (300 mg, 0.519 mmol) in acetone was added K.sub.2CO.sub.3
(143.7 mg, 1.03 mmol) and methyl Iodide (0.1 ml, 1.5594 mmol). The
resulting reaction mixture was heated at reflux for 12 hrs. The
reaction mixture was concentrated, diluted with water and extracted
with ethyl acetate. The organic layer was washed with water and
brine, dried over Na.sub.2SO.sub.4 concentrated under reduced
pressure to afford 150 mg (48.8%) of
6-Chloro-2-[4-ethoxycarbonyl-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-
-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester.
[0785] LC/MS [M+H].sup.+: 591.
Step-6:
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl-
)-4-(4-fluoro-benzyl)-piperidine-4-carboxylic acid ethyl ester
[0786] To a solution of
6-Chloro-2-[4-ethoxycarbonyl-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-
-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester (170 mg, 0.29 mol) in DCM was added trifluoroacetic acid
(0.26 ml, 2.29 mmol) drop wise in cold condition. The mixture was
allowed to stir at room temperature for one and half hour. The
organic layer was evaporated and the crude mass was diluted with
water, basified with 2N NaOH solution and extracted with ethyl
acetate. The organic layer was washed with water and brine, and
then dried over Na.sub.2SO.sub.4. Concentration of the organic
extract under vacuum afforded 110 mg (78%) of
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-f-
luoro-benzyl)-piperidine-4-carboxylic acid ethyl ester. LC/MS
[M+H].sup.+: 491.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.10 (bs, 4H), 6.32(s, 1H), 6.56 (s, 1H), 5.56 (s, 1H), 4.93
(s, 1H), 4.08 (m, 3H), 3.91 (s, 1H), 3.70 (d, 3H), 3.07 (m, 2H),
2.82 (s, 2H), 2.66 (m, 1H), 1.98 (m, 2H), 1.58 (m, 2H), 1.15 (m,
3H), 0.93 (bs, 1H). HPLC: 98.3%.
Example 83
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carboxylic acid ethyl ester
##STR00115##
[0787]
6-Chloro-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarbox-
ylic acid 4-tert-butyl ester was prepared by a process as described
in example 51.
[0788] 4-(4-Fluoro-benzyl)-piperidine-4-carboxylic acid ethyl ester
was prepared by a process similar to that described in example
82.
Step-1:
6-Chloro-7-dimethylamino-2-[4-ethoxycarbonyl-4-(4-fluoro-benzyl)--
piperidine-1-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tent-butyl ester
[0789] To a solution of
6-Chloro-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (300 mg, 0.84 mmol) in DMF was added
4-(4-Fluoro-benzyl)-piperidine-4-carboxylic acid ethyl ester (223
mg, 0.84 mmol), EDCI (209 mg, 1.09 mmol), HOBt (57 mg, 0.42 mmol)
and DIPEA (0.4 ml, 2.5 mmol) at 5-10.degree. C. The reaction
mixture was stirred at room temperature for 15 hours then diluted
with water and extracted with ethyl acetate. The organic layer was
concentrated in vacuo and subjected to column chromatography over
silica gel (3% MeOH-DCM) to afford 350 mg (69.1%) of
6-Chloro-7-dimethylamino-2-[4-ethoxycarbonyl-4-(4-fluoro-benzyl)-piperidi-
ne-1-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester. LC/MS [M+H].sup.+: 604.1.
Step-2:
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-ca-
rbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carboxylic acid ethyl
ester
[0790] To a solution of
6-Chloro-7-dimethylamino-2-[4-ethoxycarbonyl-4-(4-fluoro-benzyl)-piperidi-
ne-1-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester (350 mg,0.57 mmol) in DCM was added
trifluoroacetic acid (0.45 ml,5.7 mmol). The reaction mixture was
stirred for about 5 h then concentrated and washed with dry ether.
The resulting TFA salt was diluted with a minimum volume of water
and neutralized with aq. NaOH solution at 5-10.degree. C.
Extraction of the neutralized solution with ethyl acetate followed
by concentration afforded 285 mg (99%) of
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carboxylic acid ethyl ester. LC/MS
[M+H].sup.+: 504.6. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.09 (d, 4H), 6.60 (bs, 1H), 6.56 (s, 1H), 5.71 (bs , 1H),
4.90 (bs, 1H), 4.13 (m, 1H), 4.08 (m, 2H), 3.90 (d, 1H), 3.21 (bs,
H), 3.04 (m, 1H), 2.82 (s, 2H), 2.64 (m, 2H), 2.50 (s, 6H), 1.96
(m, 2H), 1.42 (m, 1H), 1.40 (m, 1H), 1.16 (s,3H).
[0791] HPLC: 96.3%.
Example 84
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-pyrid-
in-4-ylmethyl-piperidine-4-carbonitrile
##STR00116##
[0792]
6-Chloro-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid4-tert-butyl ester was prepared by a process as described in
example 27. Step-1: Pyridin-4-yl-methanol
[0793] To a solution of Pyridine-4-carbaldehyde (500 mg, 4.66 mmol)
in 10 ml of methanol was added NaBH.sub.4 (172 mg, 4.66 mmol) in
ice cool condition. The reaction mixture was stirred for half an
hour in ice cool condition and then it was quenched with saturated
solution of sodium sulfate and evaporated to a concentrated mass
which was then diluted with water and extracted with 10% ethanol in
ethyl acetate. The organic layer was dried over sodium sulfate and
concentrated at reduced pressure to get 500 mg (98%) of
Pyridin-4-yl-methanol. GCMS (m/z): 109.
Step-2: 4-Bromomethyl-pyridine hydrobromide
[0794] Pyridin-4-yl-methano (500 mg, 4.58 mmol) was taken in 5 ml
of 48% of aqueous solution of HBr and the reaction mixture was
subjected to reflux for 8 hours. Then the reaction mixture was
evaporated, tripped with toluene and washed with hexane to afford
4-Bromomethyl-pyridine hydrobromide. GCMS (m/z): 172.
Step-3: 4-Cyano-4-pyridin-4-ylmethyl-piperidine-1-carboxylic acid
tent-butyl ester
[0795] To a solution of DIPA (1 ml, 7.12 mmol) in THF was added
n-BuLi (3.78 ml, 7.12 mmol) in ice cool condition. Then the
reaction mixture was stirred for 1 hour at room temperature and was
cooled to -78.degree. C. To the previous solution at -78.degree. C.
was added a solution of 4-Bromomethyl-pyridine hydrobromide (749
mg, 3.56 mmol) in THF (5 ml) and stirred for another hour at
-78.degree. C. Then to that solution was added solid compound
4-fluorobenzyl bromide (900 mg, 3.56 mmol) at -78.degree. C. and
stirred at that temperature for 1 hour. The temperature of the
reaction was allowed to rise at room temperature and stirred for 14
hours. Then the reaction mixture was quenched with saturated
solution of ammonium chloride and extracted with ethyl acetate,
washed with brine, dried over sodium sulfate and concentrated to
get the crude mass which was further purified by column
chromatography over silica gel (30% ethyl acetate-hexane) to afford
510 mg (47.4%) of
4-Cyano-4-pyridin-4-ylmethyl-piperidine-1-carboxylic acid
tert-butyl ester.
[0796] LC/MS [M+H].sup.+: 302.2.
Step-4: 4-Pyridin-4-ylmethyl-piperidine-4-carbonitrile
[0797] To a solution of
4-Cyano-4-pyridin-4-ylmethyl-piperidine-1-carboxylic acid
tert-butyl ester (500 mg, 1.659 mmol) in DCM was added TFA (1.3 ml,
16.7 mmol) in ice cool condition and the reaction mixture was
stirred for 2 hours. The reaction mixture was concentrated under
reduced pressure and diluted with water, basified with 1(N) NaOH,
then extracted with ethyl acetate. Organic layer was washed with
water and brine, dried over sodium sulfate and concentrated under
reduced pressure to get 225 mg (76%) of
4-Pyridin-4-ylmethyl-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
202.2.
Step-5:
6-Chloro-2-(4-cyano-4-pyridin-4-ylmethyl-piperidine-1-carbonyl)-7-
-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester
[0798] To a solution of
6-Chloro-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (100 mg, 0.29 mmol) in DMF was added EDCI
(72.5 mg, 0.38 mmol), HOBT (19.6 mg, 0.14 mmol) and DIPEA (0.15 ml,
0.87 mmol) was added at 5.degree. C. The resulting mixture was
allowed to stir at room temperature for 30 minutes. A solution of
4-Pyridin-4-ylmethyl-piperidine-4-carbonitrile (58.5 mg, 0.29 mmol)
in DMF was added to it at 5.degree. C. and the reaction mixture was
allowed to stir at room temperature overnight. The reaction mass
was diluted with ice-water, stirred for 10 minutes and extracted
with ethyl acetate. The organic layer was washed with water and
brine, then dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure. Purification of the crude by column
chromatography over silica gel (2% MeOH-DCM) as compound eluent
afforded 90 mg (59%) of
6-Chloro-2-(4-cyano-4-pyridin-4-ylmethyl-piperidine-1-carbonyl)-7-methoxy-
-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester.
LC/MS [M+H].sup.+: 527.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 8.56 (d, 2H), 7.65 (bs, H), 7.33 (m, 2H), 6.69 (d,
H), 5.47 (m, H), 4.33 (bs, H), 4.12 (bs, 2H), 3.81 (s, 3H), 3.16
(m, H), 3.00 (m, 2H), 2.65 (m, H), 1.85 (m, 3H), 1.57 (m, H), 1.44
(s, 9H), 1.23 (s, H).
Step-6:
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl-
)-4-pyridin-4-ylmethyl-piperidine-4-carbonitrile
[0799] To a solution of
6-Chloro-2-(4-cyano-4-pyridin-4-ylmethyl-piperidine-1-carbonyl)-7-methoxy-
-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
(90 mg, 0.17 mmol) in DCM was added trifluoro acetic acid (0.13 ml,
1.71 mmol) dropwise in cold condition. The mixture was allowed to
stir at room temperature 2 hours. Then DCM was evaporated and the
crude mass was diluted with water and basified with 2N NaOH
solution, then extracted with ethyl acetate. Ethyl acetate extract
was washed with water and brine, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. Washing of the crude mass with
hexane afforded 55 mg (75%) of
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-pyri-
din-4-ylmethyl-piperidine-4-carbonitrile. LC/MS [M+H].sup.+: 427.2.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 11.91 (bs, H),
8.56 (d, 2H, J=5.0 Hz), 7.33 (s, 2H), 6.62 (m, 2H), 5.58 (s, H),
4.98 (bs, H), 4.39 (bs, H), 4.04 (m, H), 3.76 (s, 3H), 3.22 (m,
2H), 2.99 (s, 2H), 2.69 (m, H), 1.91 (s, H), 1.83 (m, 2H), 1.58 (m,
H), 1.23 (m, H). HPLC: 96.4%.
Example 85
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-pyridin-4-ylmethyl-piperidine-4-carbonitrile
##STR00117##
[0800]
6-Chloro-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarbox-
ylic acid 4-tert-butyl ester was prepared by a process as described
in example 51. Step-1: Pyridin-4-yl-methanol
[0801] To a solution of Pyridine-4-carbaldehyde (500 mg, 4.66
mmol), in 10 ml of methanol was added NaBH.sub.4 (172 mg, 4.66
mmol) in ice cool condition. Then the reaction mixture was stirred
for half an hour in ice cool condition and then it was quenched
with saturated solution of sodium sulfate and evaporated to a
concentrated mass which was then diluted with water and extracted
with 10% ethanol in ethyl acetate. The organic layer was dried over
sodium sulfate and concentrated at reduced pressure to get 500 mg
(98%) of Pyridin-4-yl-methanol. GCMS (m/z): 109.
Step-2: 4-Bromomethyl-pyridine hydrobromide
[0802] Pyridin-4-yl-methano (500 mg, 4.58 mmol) was taken in 5 ml
of 48% of aqueous solution of HBr and the reaction mixture was
subjected to reflux for 8 hours. Then the reaction mixture was
evaporated, tripped with toluene and washed with hexane to afford
4-Bromomethyl-pyridine hydrobromide. GCMS (m/z): 172.
Step-3: 4-Cyano-4-pyridin-4-ylmethyl-piperidine-1-carboxylic acid
tert-butyl ester
[0803] To a solution of DIPA (1 ml, 7.12 mmol) in 5 ml of THF and
to it was added n-BuLi (3.78 ml, 7.12mmol) in ice cool condition.
The reaction mixture was stirred for 1 hour at room temperature and
cooled to -78.degree. C. To that solution was added a solution of
4-Bromomethyl-pyridine hydrobromide (749 mg, 3.56 mmol) in 5 ml of
THF at -78.degree. C. and stirred for another hour at -78.degree.
C. Then to that solution was added solid compound 4-fluorobenzyl
bromide (900 mg, 3.56 mmol) at -78.degree. C. and stirred at that
temperature for 1 hour. The temperature of the reaction mixture was
allowed to rise at room temperature and stirred for 14 hours. The
reaction mixture was quenched with saturated solution of ammonium
chloride and extracted with ethyl acetate, washed with brine, dried
over sodium sulfate and concentrated to get the crude mass which
was further purified by column chromatography (Si-gel, 30% ethyl
acetate-hexane) to afford 510 mg (47.4%) of
4-Cyano-4-pyridin-4-ylmethyl-piperidine-1-carboxylic acid
tert-butyl ester. LC/MS [M+H].sup.+: 302.2.
Step-4: 4-Pyridin-4-ylmethyl-piperidine-4-carbonitrile
[0804] To a solution of
4-Cyano-4-pyridin-4-ylmethyl-piperidine-1-carboxylic acid
tert-butyl ester (500 mg, 1.66 mmol) in DCM was added TFA (1.3 ml,
16.7 mmol) in ice cool condition and the reaction mixture was
stirred for 2 hours. Then the reaction mixture was concentrated
under reduced pressure and diluted with water, basified with 1(N)
NaOH, then extracted with ethyl acetate. The organic layer was
washed with water and brine, dried over sodium sulfate and
concentrated under reduced pressure to afford 225 mg (76%) of
4-Pyridin-4-ylmethyl-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
202.2
Step-5:
6-Chloro-2-(4-cyano-4-pyridin-4-ylmethyl-piperidine-1-carbonyl)-7-
-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester
[0805] To a solution of
6-Chloro-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (114 mg, 0.32 mmol) in 1 ml of DMF, EDCI
(183 mg, 0.96 mmol), HOBT (22 mg, 0.16 mmol) and DIPEA (0.16 ml,
0.96 mmol) was added at 10.degree. C. The resulting mixture was
allowed to stir at room temperature for 30 minutes. Then a solution
of 4-Pyridin-4-ylmethyl-piperidine-4-carbonitrile (64 mg, 0.32
mmol) in 0.5 ml DMF was added to it at 10.degree. C. and the
reaction mixture was allowed to stir at room temperature overnight.
The reaction mass was diluted with ice-water, stirred for 10
minutes and extracted with ethyl acetate. Ethyl acetate layer was
washed with water and brine, then dried over Na.sub.2SO.sub.4 and
concentrated under vacuum. Purification of the crude by column
chromatography over silica-gel (2-3% MeOH-DCM) afforded 100 mg
(58%) of
6-Chloro-2-(4-cyano-4-pyridin-4-ylmethyl-piperidine-1-carbonyl)-7-dimethy-
lamino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester. LC/MS [M+H].sup.+: 540.3.
Step-6:
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-ca-
rbonyl)-4-pyridin-4-ylmethyl-piperidine-4-carbonitrile
[0806] To a solution of
6-Chloro-2-(4-cyano-4-pyridin-4-ylmethyl-piperidine-1-carbonyl)-7-dimethy-
lamino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester (100 mg, 0.185 mmol) in DCM was added trifluoroacetic acid
(0.14 ml, 1.85 mmol) drop wise at cold condition. The mixture was
allowed to stir at room temperature for one and half an hour. Then
DCM was evaporated and the crude mass was diluted with water,
basified with 2N NaOH solution and extracted with ethyl acetate.
The organic layer was washed with water and brine, and dried over
Na.sub.2SO.sub.4. Concentration of the organic layer under reduced
pressure afforded 50 mg (61%) of
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-pyridin-4-ylmethyl-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
442.8. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 8.56 (d,
2H, J=4.96), 7.33 (s, 2H), 6.61 (s, 1H), 6.57 (s, 1H), 5.74 (s,
1H), 4.95 (brs, 1H), 4.40 (m, 1H), 4.09 (m, 1H), 3.22 (m, 2H), 3.00
(brs, 2H), 2.70 (m, 1H), 2.57 (m, 6H), 1.83 (m, 4H), 1.58 (m, 1H).
HPLC: 97.96%
Example 86
(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-ben-
zyl)-4-hydroxymethyl-piperidin-1-yl]-methanone
##STR00118##
[0807] Step-1: 4-(4-Fluoro-benzyl)-piperidine-1,4-dicarboxylic acid
1-tert-butyl ester 4-ethyl ester
[0808] To a solution of of DIPEA (1.3 ml, 9.33 mmol) in dry THF,
was added n-BuLi (10.88 mmol) solution dropwise at 0.degree. C. The
mixture was allowed to stir for 1 hr at room temperature. To this
mixture a solution of Piperidine-1,4-dicarboxylic acid 1-tert-butyl
ester 4-ethyl ester (2.0 g, 7.77 mmol) in dry THF was added
dropwise at -78.degree. C. The resulting mixture was allowed to
stir for two hours at -78.degree. C. to 0.degree. C. Then a
solution of 4-Fluoro benzylbromide (0.97 ml, 7.77 mmol) in dry THF
was added dropwise at -78.degree. C. and the resulting mixture was
allowed to stir at room temperature overnight. The reaction was
quenched with saturated NH.sub.4Cl solution in cold condition and
stirred at room temperature for 30 minutes. THF layer was separated
and the aqueous layer was extracted with ethyl acetate. The
combined organic layers (THF and ethyl acetate) was washed with
water and brine, then dried over Na.sub.2SO.sub.4and concentrated
under reduced pressure Purification of the crude by column
chromatography (Si-gel, 4% ethyl acetate-hexane) afforded 2.3 g
(81%) of 4-(4-Fluoro-benzyl)-piperidine-1,4-dicarboxylic acid
1-tert-butyl ester 4-ethyl ester. LC/MS [M+H].sup.+: 366.3.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.08 (d, 4H,
J=7.28 Hz), 4.05 (q, 2H, J=7.04 Hz, 14.12 Hz), 3.79 (d, 2H, J=13.16
Hz), 2.79 (s, 2H), 2.75 (m, 2H), 1.88 (d, 2H, J=13.32 Hz), 1.42 (m,
2H), 1.38 (s, 9H), 1.13 (t, 3H, J=7.08 Hz, 9.44 Hz).
Step-2: 4-(4-Fluoro-benzyl)-4-hydroxymethyl-piperidine-1-carboxylic
acid tent-butyl ester
[0809] To a slurry of lithium aluminum hydride (57 mg, 1.5 mmol) in
6 ml of dry diethyl ether was added a solution of
4-(4-Fluoro-benzyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl
ester 4-ethyl ester (500 mg, 1.37 mmol) in dry diethyl ether
dropwise at 0.degree. C. with maintaining the temperature of the
reaction mixture below 10.degree. C. The resulting mixture was
stirred at 0.degree. C. for one hour and then quenched with
successive addition of water (0.057 ml), 15% aqueous NaOH (0.057
ml) and water (0.114 ml). The resultant slurry was stirred for one
hour and then filtered through a celite bed. The filtrate was dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure to
afford 4-(4-Fluoro-benzyl)-4-hydroxymethyl-piperidine-1-carboxylic
acid tert-butyl ester. LC/MS [M+H].sup.+: 324.3.
[0810] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.21 (m,
2H), 7.08 (t, 2H, J=8.84 Hz, 8.72 Hz), 4.67 (t, H, J=4.8 Hz, 4.84
Hz), 3.41 (m, 2H), 3.26 (m, 2H), 3.12 (d, 2H, J=4.76 Hz), 2.61 (s,
2H), 2.75 (m, 2H), J=13.32 Hz), 1.37 (s, 9H), 1.24 (m, 3H).
Step-3 : [4-(4-Fluoro-benzyl)-piperidin-4-yl]-methanol
[0811] To a solution of compound
4-(4-Fluoro-benzyl)-4-hydroxymethyl-piperidine-1-carboxylic acid
tert-butyl ester (430 mg, 1.33 mmol) in 6 ml of DCM was added
trifluoro acetic acid (1.02 ml, 13.3 mmol) dropwise in cold
condition. The mixture was allowed to stir at room temperature for
one hour. The reaction mixture was evaporated and the crude mass
was diluted with water, neutralized with 2N NaOH solution and
extracted with ethyl acetate. The organic layer was washed with
water and brine, and then dried over Na.sub.2SO.sub.4.
Concentration of the organic layer under reduced pressure afforded
230 mg (77%) of [4-(4-Fluoro-benzyl)-piperidin-4-yl]-methanol.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 8.31 (s,H), 7.21
(t, 2H, J=7.6 Hz, 5.92 Hz), 7.12 (t, 2H, J=8.72 Hz, 8.56 Hz), 4.85
(s, H) 3.16 (m, 2H), 3.12 (m, H), 3.03 (m, 2H), 2.65 (s, 2H),1.5
(m, 2H), 1.41 (m, 2H), 1.23 (s, H). LC/MS [M+H].sup.+: 224.2.
Step-4:
6-Chloro-2-[4-(4-fluoro-benzyl)-4-hydroxymethyl-piperidine-1-carb-
onyl]-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester
[0812] To a solution of
6-Chloro-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (231 mg, 0.67 mmol) in DMF was added EDCI
(167 mg, 0.87 mmol), HOBT (45 mg, 0.34 mmol) and DIPEA (0.35 ml
2.01 mmol) at 5.degree. C. The resulting mixture was allowed to
stir at room temperature for 30 minutes. Then a solution of
[4-(4-Fluoro-benzyl)-piperidin-4-yl]-methanol (150 mg, 0.67 mmol)
in DMF (0.5 ml) was added to the previous reaction mixture at
5.degree. C. and the reaction mixture was allowed to stir at room
temperature overnight. The reaction mass was diluted with
ice-water, stirred for 10 minutes and extracted with ethyl acetate.
The organic layer was washed with water and brine, then dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Purification of the crude by column chromatography (Si-gel, 1.5%
MeOH-DCM) afforded 80 mg (23%) of
6-Chloro-2-[4-(4-fluoro-benzyl)-4-hydroxymethyl-piperidine-1-carbonyl]-7--
methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester. LC/MS [M+H].sup.+: 549.3. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 7.23 (m, 2H), 7.09 (t, 2H, J=8.6 Hz,
8.35 Hz), 6.67 (s, H), 5.38 (s, H), 4.76 (m, H), 3.98 (m, 2H), 3.79
(s, 3H), 3.60 (m, 2H), 3.18 (s, 2H), 2.89 (m, 2H), 2.73 (s, H),
2.67 (s, H), 2.55 (m, H), 1.43 (s, 9H), 1.26 (m, 2H).
Step-5:
(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-f-
luoro-benzyl)-4-hydroxymethyl-piperidin-1-methanone
[0813] To a solution of
6-Chloro-2-[4-(4-fluoro-benzyl)-4-hydroxymethyl-piperidine-1-carbonyl]-7--
methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester (80 mg,0.146 mmol) in 4 ml of DCM was added trifluoro acetic
acid (0.11 ml, 1.46 mmol) dropwise in cold condition. The mixture
was allowed to stir at room temperature for 2 hours. Then DCM was
evaporated and the crude mass was diluted with water, basified with
2N NaOH solution and extracted with ethyl acetate. Ethyl acetate
extract was washed with water and brine, then dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Purification of the crude by column chromatography in 100-200
silica mesh and 3.5% MeOH-DCM as compound eluent afforded 30 mg
(46%) of
(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4--
fluoro-benzyl)-4-hydroxymethyl-piperidin-1-yl]-methanone. LC/MS
[M+H].sup.+:449.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.23 (bs, 2H), 7.09 (t, 2H, J=8.76 Hz, 8.6 Hz), 6.63 (s, H),
6.55 (bs, H), 5.56 (s, H), 4.91 (bs, H), 4.73 (bs, H), 3.70 (d, 3H,
J=10.36 Hz), 3.52 (m, 4H), 3.17 (s, 3H), 2.66 (s, 2H), 1.30 (m,
4H). HPLC: 98.9%.
Example 87
(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluo-
ro-benzyl)-4-hydroxymethyl-piperidin-1-yl]-methanone
##STR00119##
[0814] [4-(4-Fluoro-benzyl)-piperidin-4-yl]-methanol was prepared
by a process as described in example 86. Step-1:
6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid
1-(6-chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbo-
nyl)-4-(4-fluoro-benzyl)-piperidin-4-ylmethyl ester
[0815] To a solution of
6-Chloro-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (150 mg, 0.42 mmol) in 0.5 ml of DMF, EDCI
(104.8 mg, 0.55 mmol), HOBT (28.4 mg, 0.21 mmol) & DIPEA (0.22
ml 1.3 mmol) was added at 5.degree. C. The resulting mixture was
allowed to stir at room temperature for 30 minutes. Then a solution
of [4-(4-Fluoro-benzyl)-piperidin-4-yl]-methanol* (94 mg, 0.42
mmol) in 0.3 ml DMF was added to it at 5.degree. C. and the
reaction mixture was allowed to stir at room temperature overnight.
The reaction mass was diluted with ice-water, stirred for 10
minutes and extracted with ethyl acetate. Ethyl acetate layer was
washed with water and brine, then dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. Purification of the crude by
column chromatography (Si-gel, 2% MeOH-DCM) 130 mg of material
showed desired mass as degradation. The material in DCM was added
trifluoro acetic acid (0.75 ml, 9.7 mmol) dropwise in cold
condition. The mixture was allowed to stir at room temperature for
one hour. Then DCM was evaporated and the crude mass was diluted
with water, basified with 2N NaOH solution and extracted with ethyl
acetate. Ethyl acetate extract was washed with water and brine,
then dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. Purification of the crude by column chromatography
(Si-gel, 2% MeOH-DCM) afforded 60 mg (59%) of
6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
oxylic acid
1-(6-chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidin-4-ylmethyl ester. LC/MS [M+H].sup.+:
700.6.
Step-3:
(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[-
4-(4-fluoro-benzyl)-4-hydroxymethyl-piperidin-1-yl]-methanone
[0816] To a solution of
6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid
1-(6-chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbo-
nyl)-4-(4-fluoro-benzyl)-piperidin-4-ylmethyl ester (60 mg,0.085
mmol) in THF-H.sub.2O (3:1) was added LiOH.H.sub.2O (7.2 mg, 0.171
mmol) in cold condition. The reaction mass was allowed to stir at
room temperature for one hour, concentrated. The residue was
diluted with water, and then extracted with ethyl acetate. The
organic layer was washed with water and brine, then dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. Washing
of the crude mass with hexane afforded 30 mg (76%) of
(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-flu-
oro-benzyl)-4-hydroxymethyl-piperidin-1-yl]-methanone. LC/MS
[M+H].sup.+: 462.1. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.23 (s, 2H), 7.09 (t, 2H, J=8.8 Hz, 8.64 Hz), 6.60 (s, H),
6.55 (bs, H), 5.74 (s,H), 4.90 (bs, H), 4.74 (s, H), 3.54 (m, 4H),
3.17 (s, 3H), 2.66 (s, 2H), 2.55 (s, 6H), 1.35 (m, 4H), 1.09 (m,
H). HPLC: 97.5%.
Example 88
6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid [1-(4-fluoro-benzyl)-4-hydroxy-piperidin-4-ylmethyl]-amide
##STR00120##
[0818]
6-Chloro-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester was prepared by a process as described in
example 27.
Step-1: 1-(4-Fluoro-benzyl)-piperidin-4-one
[0819] To a stirred solution of Piperidin-4-one (2 g, 13.0 mmol) in
acetonitrile was added K.sub.2CO.sub.3 (5.40 g, 39.0 mmol) and
1-Bromomethyl-4-fluoro-benzene (1.5 ml, 11.7 mmol) at 0.degree. C.
The reaction mixture was stirred at room temperature for overnight.
The reaction mixture was diluted with water and extracted with
chloroform. The organic layer was washed with water, dilutes NaOH
and dried over Na.sub.2SO.sub.4. The organic layer was concentrated
in reduced pressure to afford 2.93 g of
1-(4-Fluoro-benzyl)-piperidin-4-one. LC/MS [M+H].sup.+: 208.0.
Step-2: 1-(4-Fluoro-benzyl)-4-hydroxy-piperidine-4-carbonitrile
[0820] To a solution of 1-(4-Fluoro-benzyl)-piperidin-4-one (2.93
g, 10.9 mmol) in water was added potassium cyanide (2.6 g, 25.2
mmol) and aquous solution of NaHSO3 (2.6 g, 25.2 mmol). The
reaction mixture was stirred for 1 hour. The reaction mixture was
extracted with chloroform and washed with water. The organic layer
was concentrated to afford 3.3 g of
1-(4-Fluoro-benzyl)-4-hydroxy-piperidine-4-carbonitrile.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 7.30 (m, H,),7.25
(m, H), 6.99(m,2H), 3.48 (s,2H,), 2.71 (m,2H), 2.55 (bs, H), 2.39
(m, 2H), 2.09 (m,2H), 1.87 (m, 2H).
Step-3: 4-Aminomethyl-1-(4-fluoro-benzyl)-piperidin-4-ol
[0821] To a solution of
1-(4-Fluoro-benzyl)-4-hydroxy-piperidine-4-carbonitrile (1 g, 4.2
mmol) in diethyl ether was added lithium aluminium hydride (324 mg,
8.5 mmol) portionwise. The reaction mixture was stirred at room
temperature for 2 hours and quenched (0.3 mlwater, 0.3 ml 15% NaOH,
0.6 mlwater). The precipitated solid was filtered off through
celite bed. The organic layer was concentrated under reduced
pressure to afford 730 mg of
4-Aminomethyl-1-(4-fluoro-benzyl)-piperidin-4-ol. LC/MS
[M+H].sup.+: 239.4.
Step-4:
6-Chloro-2-{[1-(4-fluoro-benzyl)-4-hydroxy-piperidin-4-ylmethyl]--
carbamoyl}-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester
[0822] To a solution of
6-Chloro-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (100 mg, 0.29 mmol) in DMF was added of
4-Aminomethyl-1-(4-fluoro-benzyl)-piperidin-4-ol (69 mg, 0.29
mmol), EDCI (72 mg, 0.38 mmol), HOBt (20 mg, 0.15 mmol) and DIPEA
(0.15 ml, 0.87 mmol) at 5-10.degree. C. The reaction mixture was
stirred at room temperature for 16 hours. The reaction mixture was
diluted with water and extracted with ethyl acetate. The organic
layer was concentrated in vacuum and purified through column
chromatography (Si-gel, 2% MeOH-DCM) to afford 60 mg (36.5%) of
6-Chloro-2-{[1-(4-fluoro-benzyl)-4-hydroxy-piperidin-4-ylmethyl]-carbamoy-
l}-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester. LC/MS [M+H].sup.+: 564.4.
Step-5:
6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid [1-(4-fluoro-benzyl)-4-hydroxy-piperidin-4-ylmethyl]-amide
[0823] To a solution of
6-Chloro-2-{[1-(4-fluoro-benzyl)-4-hydroxy-piperidin-4-ylmethyl]-carbamoy-
l}-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester (60 mg, 0.11 mmol)) in DCM was added
trifluoroacetic acid (0.1 ml). The reaction mixture was stirred for
about 5 h then concentrated and washed with dry ether. The
resulting TFA salt was diluted with a minimum volume of water and
neutralized with aq. NaOH solution at 5-10 .degree. C. Extraction
of the neutralized solution with ethyl acetate followed by
concentration afforded 40 mg (81.1%) of
6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid [1-(4-fluoro-benzyl)-4-hydroxy-piperidin-4-ylmethyl]-amide.
LC/MS [M+H].sup.+: 464.44. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 7.61 (bs, 1H), 7.30 (t, 2H), 7.11 (t, 2H), 6.65 (d,
2H), 5.63 (s, 1H), 4.56 (m, 1H), 4.40 (s, 1H), 3.71 (s, 3H), 3.41
(m, 4H), 3.14 (m, 3H), 2.37 (bs, 2H), 2.28 (m, 2H), 1.98 (m, 1H),
1.67 (m, 1H), 1.40 (1H). HPLC: 92.9%.
Example 89
6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid [1-(4-fluoro-benzyl)-4-hydroxy-piperidin-4-ylmethyl]-amide
##STR00121##
[0824] 4-Aminomethyl-1-(4-fluoro-benzyl)-piperidin-4-ol was
prepared by a process described in example 88. Step 1:
6-Chloro-7-dimethylamino-2-{[1-(4-fluoro-benzyl)-4-hydroxy-piperidin-4-yl-
methyl]- carbamoyl}-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester
[0825] To a solution of
6-Chloro-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (67 mg,0.28 mmol) in DMF was added
4-Aminomethyl-1-(4-fluoro-benzyl)-piperidin-4-ol (100 mg,0.28
mmol), EDCI (69 mg,0.36 mmol), HOBT (19 mg,0.14 mmol) and DIPEA
(0.15 ml, 0.84 mmol) at 5-10.degree. C. The reaction mixture was
stirred at room temperature for 15 hours then diluted with water
and extracted with ethyl acetate. The ethyl acetate layer was
concentrated in vacuo to afford 110 mg (68%) of
6-Chloro-7-dimethylamino-2-{[1-(4-fluoro-benzyl)-4-hydroxy-piperidin-4-
-ylmethyl]-carbamoyl}-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester. LC/MS [M+H].sup.+: 577.4.
Step-2:
6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbo-
xylic
acid[1-(4-fluoro-benzyl)-4-hydroxy-piperidin-4-ylmethyl]-amide
[0826] To a solution of
6-Chloro-7-dimethylamino-2-{[1-(4-fluoro-benzyl)-4-hydroxy-piperidin-4-yl-
methyl]-carbamoyl}-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester (110 mg,0.19 mmol) in DCM was added
trifluoroacetic acid (0.3 ml, 3.9 mmol). The reaction mixture was
stirred for about 5 h then concentrated and washed with dry ether.
The resulting TFA salt was diluted with a minimum volume of water
and neutralized with aq. NaOH solution at 5-10.degree. C.
Extraction of the neutralized solution with ethyl acetate followed
by concentration afforded 53 mg (58.4%) of
6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid [1-(4-fluoro-benzyl)-4-hydroxy-piperidin-4-ylmethyl]-amide.
LC/MS [M+H].sup.+: 477.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 7.60(m, H,),7.30(m,2H),7.11(m,2H), 6.77(s, H,),
6.62(s,H), 4.54 (m, H), 4.39 (s, H), 3.38 (m, 2H), 3.15 (m, 3H),
2.56 (s, 6H), 2.37 (m, 2H), 2.27 (m, 2H), 1.98 (m, H). HPLC:
93.3%.
Example 90
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidine-4-carbonitrile
##STR00122##
[0827]
6-Chloro-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarbox-
ylic acid 4-tert-butyl ester was prepared by a process as described
in example 51. Step-1:
4-Cyano-4-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic
acid tert-butyl ester
[0828] To a solution of of DIPA (1.6 ml, 11.41 mmol) in dry THF,
was added n-BuLi (13.31 mmol) solution dropwise at 0.degree. C. The
mixture was allowed to stir for 1 hr at room temperature. To this
mixture a solution of N-boc-4-cyanopipyridine (2.0 g, 9.51 mmol) in
dry THF was added dropwise at -78.degree. C. The resulting mixture
was allowed to stir for two hours at -78.degree. C. to 0.degree. C.
Then a solution of 4-Fluoro benzaldehyde (1.1 ml, 9.51 mmol) in dry
THF was added dropwise at -78.degree. C. and the resulting mixture
was allowed to stir at room temperature overnight. The reaction was
quenched with saturated NH.sub.4Cl solution in cold condition and
stirred at room temperature for 30 minutes. THF layer was separated
and the aqueous layer was extracted with ethyl acetate. The
combined organic layers (THF and ethyl acetate) was washed with
water and brine, then dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure Purification of the crude mass by column
chromatography(Si-gel, 20% ethyl acetate-hexane) afforded 1.2 g
(38%) of
4-Cyano-4-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidine-1-carbox-
ylic acid tert-butyl ester. LC/MS [M+H].sup.+: 335.2. .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.43 (t, 2H, J=7.6 Hz, 5.72
Hz), 7.08 (t, 2H, J=8.32 Hz, 8.44 Hz), 4.51 (s, H), 4.14 (m, 2H),
2.95 (m, 2H), 2.29(s, H), 2.22 (d, H, J=13.44 Hz), 1.54(s, H), 1.49
(s, H), 1.43 (s, 9H).
Step-2:
4-[(4-Fluoro-phenyl)-hydroxy-methyl]-piperidine-4-carbonitrile
[0829] To a solution of
4-Cyano-4-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic
acid tert-butyl ester (1.2 g, 3.59 mmol) in DCM was added trifluoro
acetic acid (2.76 ml, 35.9 mmol) dropwise in cold condition. The
mixture was allowed to stir at room temperature for one and half an
hour. Then DCM was evaporated and the crude mass was diluted with
water, neutralized with 2N NaOH solution and extracted with ethyl
acetate. Ethyl acetate extract was washed with water and brine, and
then dried over Na.sub.2SO.sub.4. Concentration of the organic
extract under reduced pressure afforded 700 mg (83%) of
4-[(4-Fluoro-phenyl)-hydroxy-methyl]-piperidine-4-carbonitrile.
LC/MS [M+H].sup.+: 235.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 7.45 (t, 2H, J=6.8 Hz, 6.68 Hz), 7.19 (t, 2H, J=8.8
Hz, 8.68 Hz), 6.09 (s, H), 4.47 (s, H), 2.93 (d, H, J=12.28 Hz),
2.83 (d, H, J=12.64 Hz), 2.61 (t, H, J=12.4 Hz, 12.6 Hz), 2.02 (m,
H), 1.45 (m, H), 1.14 (d, H, J=12.4 Hz).
Step-3:
6-Chloro-2-{4-cyano-4-1-[(4-fluoro-phenyl)-hydroxy-methyl]-piperi-
dine-1-carbonyl}-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-4-carboxyli-
c acid tent-butyl ester
[0830] To a solution of
6-Chloro-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (100 mg, 0.280 mmol) in 1 ml of DMF, EDCI
(161 mg, 0.84 mmol), HOBT (19mg, 0.14 mmol) and DIPEA (0.14 ml,
0.84 mmol) was added at 10.degree. C. The resulting mixture was
allowed to stir at room temperature for 30 minutes. Then a solution
of 4-[(4-Fluoro-phenyl)-hydroxy-methyl]-piperidine-4-carbonitrile
(66 mg, 0.28 mmol) in 0.5 ml DMF was added to it at 10.degree. C.
and the reaction mixture was allowed to stir at room temperature
overnight. The reaction mass was diluted with ice-water, stirred
for 10 minutes and extracted with ethyl acetate. Ethyl acetate
layer was washed with water and brine, then dried over
Na.sub.2SO.sub.4 and concentrated under vacuum. Purification of the
crude mass by column chromatography (Si-gel, 2-3) % MeOH-DCM)
afforded 110 mg (68%) of
6-Chloro-2-{4-cyano-4-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidine-1-car-
bonyl -7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester. LC/MS [M+H].sup.+: 573.2.
Step-4:
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-ca-
rbonyl)-4-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidine-4-carbonitrile
[0831] To a solution of
6-Chloro-2-{4-cyano-4-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidine-1-car-
bonyl}-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester (100 mg, 0.174 mmol) in DCM was added
trifluoroacetic acid (0.14 ml, 1.85 mmol) drop wise in cold
condition. The mixture was allowed to stir at room temperature for
one and half an hour. Then DCM was evaporated and the crude mass
was diluted with water, basified with 2N NaOH solution and
extracted with ethyl acetate. The organic layer was washed with
water and brine and then dried over Na.sub.2SO.sub.4. Concentration
of the organic layer under reduced pressure afforded 50 mg (61%) of
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-c-
arbonyl)-4-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidine-4-carbonitrile.
LC/MS [M+H].sup.+: 473.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 7.48(brs, 1H), 7.21(m,2H), 6.63(s,2H), 6.22(brs,1H),
4.93(m,1H), 4.46(m,1H), 4.02(m,1H), 3.24(m,1H), 2.64(brs,6H), 2.18
to 1.15(8H). HPLC: 98.4%.
Example 91
1-[6-Chloro-7-dimethylamino-4-(2-dimethylamino-ethyl)-3,4-dihydro-2H-benzo-
[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00123##
[0832]
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared as
described in example 51. Step-1:
1-[6-Chloro-7-dimethylamino-4-(2-hydroxy-ethyl)-3,4-dihydro-2H-benzo[1,4]-
oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0833] To a solution of
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile (150 mg, 0.33 mmol)
in 1.0 ml of DMF, was added K.sub.2CO.sub.3 (97 mg, 0.66 mmol)
& 2-Bromo ethanol (0.075 ml, 1.069 mmol). The resulting mixture
was heated at 55.degree. C. for 36 hrs. Then reaction mass was
diluted with water and extracted with ethyl acetate. Organic
extract was washed with water and brine, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Purification of the crude over column chromatography (Si-gel, 1%
MeOH-DCM) afforded 100 mg (61%) of
1-[6-Chloro-7-dimethylamino-4-(2-hydroxy-ethyl)-3,4-dihydro-2H-benzo[1,4]-
oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile.
LC/MS [M+H].sup.+: 501.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 7.34 (bs, 2H), 7.19 (t, 2H, J=8.6 Hz, 8.52 Hz), 6.73
(s, H), 6.62 (d, H, J=17.32 Hz), 4.99 (s, H), 4.71 (m, H), 4.38 (m,
H), 4.10 (m, 2H), 3.55 (s, 2H), 3.43 (m, 2H), 2.95 (d, 2H, J=10.56
Hz), 2.69 (m, H), 2.58 (s, 6H), 1.82 (m, H), 1.78 (m, 2H), 1.70 (m,
H), 1.54 (m, H).
Step-2: Methanesulfonic acid
2-{6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-dimet-
hylamino-2,3-dihydro-benzo[1,4]oxazin-4-yl}-ethyl ester
[0834] To a solution of
1-[6-Chloro-7-dimethylamino-4-(2-hydroxy-ethyl)-3,4-dihydro-2H-benzo[1,4]-
oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
(100 mg,0.20 mmol) in 3 ml of DCM was added triethyl amine (0.06
ml, 0.40 mmol) and Mesyl chloride (0.02 ml, 0.24 mmol) in cold
condition and the mixture was stirred at rt for 4 hrs. Then the
reaction mass in DCM was washed with bicarbonate solution followed
by water and brine, dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure. The crude was washed with hexane to afford
130 mg of Methanesulfonic acid
2-{6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-dimet-
hylamino-2,3-dihydro-benzo[1,4]oxazin-4-yl}-ethyl ester. LC/MS
[M+H].sup.+: 579.4.
Step-3 :
1-[6-Chloro-7-dimethylamino-4-(2-dimethylamino-ethyl)-3,4-dihydr-
o-2H-benzo[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbon-
itrile
[0835] A solution of
2-{6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-dimet-
hylamino-2,3-dihydro-benzo[1,4]oxazin-4-yl}-ethyl ester (130 mg,
0.22 mmol) and 6 ml 0 f Dimethyl amine (2M solution in THF) was
heated in a seal tube at 80.degree. C. overnight. The reaction
mixture was evaporated under reduced pressure. Purification of the
crude over column chromatography (Si-gel, 2.5% MeOH-DCM) afforded
70 mg (59%) of
1-[6-Chloro-7-dimethylamino-4-(2-dimethylamino-ethyl)-3,4-dihydro-2H-benz-
o[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile.
LC/MS [M+H].sup.+: 428.3. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 7.35 (bs, 2H), 7.19 (t, 2H, J=8.8 Hz), 6.87(s, H),
6.64 (d, H, J=19.8 Hz), 5.13 (s, H), 4.37 (d, H, J=13.44), 4.14 (t,
H, J=15.48 Hz, 14.72 Hz), 3.53 (bs, 2H), 3.40 (m, H), 3.01 (s, 2H),
2.73 (s, H), 2.63 (m, 4H), 2.58 (s, 6H), 2.50 (s, 6H), 1.82 (m,
2H), 1.79 (m, H), 1.53 (m, H). HPLC: 97.7%.
Example 92
1-[6-Chloro-4-(2-dimethylamino-ethyl)-7-methoxy-3,4-dihydro-2H-benzo[1,4]o-
xazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00124##
[0837]
1-[6-Chloro-4-(2-dimethylamino-ethyl)-7-methoxy-3,4-dihydro-2H-benz-
o[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
was prepared by a process similar to that described in example 91.
LC/MS [M+H].sup.+: 515.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 7.34 (bs, 2H), 7.19 (t, 2H), 6.78 (bs, 1H), 6.61 (m,
1H), 5.06 (m, 2H), 4.39 (d, 1H), 4.06 (m, 2H), 3.42 (s, 3H), 3.30
(m, 2H), 3.19 (m, 2H), 2.95 (s, 2H), 2.70 (s, 1H), 2.26 (bs, 6H),
1.90 (m, 2H), 1.74 (m, 1H), 1.53 (m, 1H), 1.23 (s, 1H). HPLC:
97.5%.
Example 93
(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-ben-
zyl)-4-imidazol-1-ylmethyl-piperidin-1-yl]-methanone
##STR00125##
[0838] Step-1:
4-(4-Fluoro-benzyl)-4-methanesulfonyloxymethyl-piperidine-1-carboxylic
acid tert-butyl ester
[0839] To a solution of
4-(4-Fluoro-benzyl)-4-hydroxymethyl-piperidine-1-carboxylic acid
tert-butyl ester (400 mg,1.24 mmol) in DCM was added triethyl amine
(0.52 ml, 3.71 mmol) followed by methane sulfonyl chloride (0.12
ml, 1.48 mmol) at cold condition. The reaction mixture was allowed
to stir at room temperature for 5 hrs. Then the reaction mass was
diluted with more DCM and washed with sodium bicarbonate solution
followed by water and brine, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The crude mass thus obtained
was washed with hexane and dried under reduced pressure to get 430
mg (86.6%) of
4-(4-Fluoro-benzyl)-4-methanesulfonyloxymethyl-piperidine-1-carboxylic
acid tert-butyl ester. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.20 (t, 2H), 7.13 (t, 2H), 3.93 (s, 2H), 3.47 (m, 2H), 3.39
(m, H), 3.34 (m, H), 3.22 (s, 3H), 2.69 (s, 2H), 1.38 (s, 9H), 1.34
(m, 4H).
Step-2 :
4-(4-Fluoro-benzyl)-4-imidazol-1-ylmethyl-piperidine-1-carboxyli- c
acid tert-butyl ester
[0840] To a solution of
4-(4-Fluoro-benzyl)-4-methanesulfonyloxymethyl-piperidine-1-carboxylic
acid tert-butyl ester (400 mg, 1.27 mmol) in DMF was added
Cs.sub.2CO.sub.3 (826 mg, 2.54 mmol). To this mixture, a solution
of 1H-Imidazole (86 mg, 1.27 mmol) in 0.5 ml of DMF was added in
cold condition and the resulting mixture was allowed to heat at
80.degree. C. for 38 hrs. Then the reaction mass was cooled and
diluted with water, extracted with ethyl acetate. The organic layer
was washed with water and brine, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. Purification of the crude by
column chromatography (Si-gel, 1.5% MeOH-DCM) afforded 180 mg (38%)
of
4-(4-Fluoro-benzyl)-4-imidazol-1-ylmethyl-piperidine-1-carboxylic
acid tert-butyl ester. LC/MS [M+H].sup.+: 374.2. .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. (ppm): 7.58 (s, H), 7.15 (m, 5H), 6.89
(s, H), 5.76 (s, H), 3.98 (s, 2H), 3.42 (s, 4H), 2.67 (s, 2H) 1.31
(s, 9H), 1.15 (m, 3H).
Step-3: 4-(4-Fluoro-benzyl)-4-imidazol-1-ylmethyl-piperidine
[0841] To a solution of
4-(4-Fluoro-benzyl)-4-imidazol-1-ylmethyl-piperidine-1-carboxylic
acid tert-butyl ester (180 mg,0.48 mmol) in 2 ml of DCM was added
trifluoro acetic acid (0.37 ml, 4.82 mmol) dropwise in cold
condition. The mixture was allowed to stir at room temperature for
90 minutes. The organic layer was evaporated and the crude mass was
diluted with water, neutralized with 2N NaOH solution and extracted
with ethyl acetate. The organic layer was washed with water, brine
and dried over Na.sub.2SO.sub.4. Concentration of the organic layer
under reduced pressure afforded 120 mg (91%) of
4-(4-Fluoro-benzyl)-4-imidazol-1-ylmethyl-piperidine. LC/MS
[M+H].sup.+: 274.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.55 (s, H), 7.12 (m, 5H), 6.89 (s, H), 3.93 (s, 2H), 2.77
(bs, 4H), 2.63 (s, 2H) 1.23 (m, 2H), 1.15 (m, 2H).
Step-4:
6-Chloro-2-[4-(4-fluoro-benzyl)-4-imidazol-1-ylmethyl-piperidine--
1-carbonyl]-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester
[0842] To a solution of
6-Chloro-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid-4-tert-butyl ester (100 mg, 0.29 mmol) in 0.5 ml of DMF was
added EDCI (72.5 mg, 0.38 mmol), HOBT (19.6 mg, 0.145 mmol) and
DIPEA (0.15 ml, 0.87 mmol) at 5.degree. C. The resulting mixture
was allowed to stir at room temperature for 30 minutes. Then a
solution of 4-(4-Fluoro-benzyl)-4-imidazol-1-ylmethyl-piperidine
(79.5 mg, 0.29 mmol) in DMF (0.3 ml) was added to it at 5.degree.
C. and the reaction mixture was allowed to stir at room temperature
overnight. The reaction mass was diluted with ice-water, stirred
for 10 minutes and extracted with ethyl acetate. Ethyl acetate
layer was washed with water and brine, then dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Purification of the crude by column chromatography (Si-gel, 1.5%
MeOH-DCM) afforded 120 mg (69%) of
6-Chloro-2-[4-(4-fluoro-benzyl)-4-imidazol-1-ylmethyl-piperidine-1-carbon-
yl]-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester. LC/MS [M+H].sup.+: 599.4. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 7.61 (s, 2H), 7.19 (m, 2H), 7.13 (m,
3H), 6.91 (d, H, J=6.4 Hz), 6.60 (d, H, J=4.48 Hz), 5.28 (bs, H),
4.03 (d, 2H, J=14.56 Hz), 3.89 (m, H), 3.79 (s, 3H), 3.65 (m, 4H),
3.47 (m, H), 2.74 (s, H), 2.68 (m, H), 1.42 (s, 9H), 1.26 (m, 4H),
0.84 (m, H).
Step-5:
(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-f-
luoro-benzyl)-4-imidazol-1-ylmethyl-piperidin-1-yl]-methanone
[0843] To a solution of
6-Chloro-2-[4-(4-fluoro-benzyl)-4-imidazol-1-ylmethyl-piperidine-1-carbon-
yl]-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester (110 mg,0.18 mmol) in 3 ml of DCM was added
trifluoro acetic acid (0.14 ml, 1.84 mmol) dropwise in cold
condition. The mixture was allowed to stir at room temperature for
two hours. Then DCM was evaporated and the crude mass was diluted
with water, basified with 2N NaOH solution and extracted with ethyl
acetate. The organic layer was washed with water and brine, then
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. Purification of the crude by column chromatography
(Si-gel, 3% MeOH-DCM) afforded 55 mg (60%) of
(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-[4-(4-fluoro-be-
nzyl)-4-imidazol-1-ylmethyl-piperidin-1-yl]-methanone. LC/MS
[M+H].sup.+: 499.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.61 (s, H), 7.18 (m, 5H), 6.91 (d, H, J=4.44 Hz), 6.61 (s,
H), 6.48 (d, H, J=7.04 Hz),5.54 (s, H), 4.89 (bs, H), 4.02 (d, 2H,
J=21.96 Hz), 3.71 (s, 3H), 3.66 (m, 2H), 3.51 (m, H), 3.23 (m, H),
3.13 (m, H), 2.73 (m, 2H), 1.33 (m, 4H), 0.84 (m, H). HPLC:
98.3%.
Example 94
1-(6-Chloro-7-ethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fluo-
ro-benzyl)-piperidine-4-carbonitrile
##STR00126##
[0844]
1-(7-Bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4--
(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared by a
process described in example 57. Step-1:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-ethyl-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
[0845] To a solution of
1-(7-Bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-flu-
oro-benzyl)-piperidine-4-carbonitrile (200 mg, 0.34 mmol) in
toluene was degassed with argon and was added tetrabutyltin (79.2
mg, 0.34 mmol) and [Pd(PPh.sub.3).sub.4] (1.57 mg, 0.002 mmol). The
reaction mixture was refluxed overnight. The reaction mixture was
concentrated and partitioned in 1:1 acetonitrile-hexane. The
acetonitrile solution was concentrated under reduced pressure and
crude was purified over column chromatography (Si-gel, 10% ethyl
acetate-hexane) to afford 180 mg (97.7%) of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-ethyl-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester.
LC/MS [M+H].sup.+: 542.2.
Step-2:
1-(6-Chloro-7-ethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0846] To a solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-ethyl-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (180
mg, 0.33 mmol)) in DCM was added trifluoroacetic acid (1 ml). The
reaction mixture was stirred for about 5 h then concentrated and
washed with dry ether. The resulting TFA salt was diluted with a
minimum volume of water and neutralized with aq. NaOH solution at
5-10.degree. C. Extraction of the neutralized solution with ethyl
acetate followed by concentration and preparative HPLC afforded 20
mg (13.7%) of
1-(6-Chloro-7-ethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-flu-
oro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+: 442.0.
LCMS purity: 98.6%.
Example-95
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-[(4-f-
luoro-phenyl)-hydroxy-methyl]-piperidine-4-carbonitrile
##STR00127##
[0847]
6-Chloro-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid-4-tert-butyl ester was prepared by a process as described in
example 27. Step-1:
4-Cyano-4-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic
acid tent-butyl ester
[0848] To a solution of of DIPA (1.6 ml, 11.41 mmol) in dry THF,
was added n-BuLi (13.31 mmol) solution dropwise at 0.degree. C. The
mixture was allowed to stir for 1 hr at room temperature. To this
mixture a solution of N-boc-4-cyanopipyridine (2.0 g, 9.51 mmol) in
dry THF was added dropwise at -78.degree. C. The resulting mixture
was allowed to stir for two hours at -78.degree. C. to 0.degree. C.
Then a solution of 4-Fluoro benzaldehyde (1.1 ml, 9.51 mmol) in dry
THF was added dropwise at -78.degree. C. and the resulting mixture
was allowed to stir at room temperature overnight. The reaction was
quenched with saturated NH.sub.4Cl solution in cold condition and
stirred at room temperature for 30 minutes. THF layer was separated
and the aqueous layer was extracted with ethyl acetate. The
combined organic layers (THF and ethyl acetate) was washed with
water and brine, then dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure Purification of the crude by column
chromatography (Si-gel, 20% ethyl acetate-hexane) afforded 1.2 g
(38%) of
4-Cyano-4-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic
acid tert-butyl ester. LC/MS [M+H].sup.+: 335.2. `H-NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 7.43 (t, 2H, J=7.6 Hz, 5.72 Hz), 7.08
(t, 2H, J=8.32 Hz, 8.44 Hz), 4.51 (s, H), 4.14 (m, 2H), 2.95 (m,
2H), 2.29(s, H), 2.22 (d, H, J=13.44 Hz), 1.54(s, H), 1.49 (s, H),
1.43 (s, 9H).
Step-2:
4-[(4-Fluoro-phenyl)-hydroxy-methyl]-piperidine-4-carbonitrile
[0849] To a solution of
4-Cyano-4-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic
acid tert-butyl ester (1.2 g, 3.59 mmol) in DCM was added trifluoro
acetic acid (2.76 ml, 35.9 mmol) dropwise in cold condition. The
mixture was allowed to stir at room temperature for one and half an
hour. Then DCM was evaporated and the crude mass was diluted with
water, neutralized with 2N NaOH solution and extracted with ethyl
acetate. Ethyl acetate extract was washed with water and brine, and
then dried over Na.sub.2SO.sub.4. Concentration of the organic
extract under reduced pressure afforded 700 mg (83%) of
4-[(4-Fluoro-phenyl)-hydroxy-methyl]-piperidine-4-carbonitrile.
LC/MS [M+H].sup.+: 235.2
[0850] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.45 (t,
2H, J=6.8 Hz, 6.68 Hz), 7.19 (t, 2H, J=8.8 Hz, 8.68 Hz), 6.09 (s,
H), 4.47 (s, H), 2.93 (d, H, J=12.28 Hz), 2.83 (d, H, J=12.64 Hz),
2.61 (t, H, J=12.4 Hz, 12.6 Hz), 2.02 (m, H), 1.45 (m, H), 1.14 (d,
H, J=12.4 Hz).
Step-3:
6-Chloro-2-{4-cyano-4-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidi-
ne-1-carbonyl}-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester
[0851] To a solution of
6-Chloro-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid-4-tert-butyl ester (100 mg, 0.29 mmol) in DMF was added EDCI
(72.5 mg, 0.38 mmol), HOBT (19.6 mg, 0.14 mmol) and DIPEA (0.15 ml
0.87 mmol) at 5.degree. C. The resulting mixture was allowed to
stir at room temperature for 30 minutes. Then a solution of
4-[(4-Fluoro-phenyl)-hydroxy-methyl]-piperidine-4-carbonitrile (68
mg, 0.29 mmol) in 0.3 ml DMF was added to it at 5.degree. C. and
the reaction mixture was allowed to stir at room temperature
overnight. The reaction mass was diluted with ice-water, stirred
for 10 minutes and extracted with ethyl acetate. Ethyl acetate
layer was washed with water and brine, then dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Purification of the crude by column chromatography (Si-gel, 0.75%
MeOH-DCM) afforded 155 mg (96%) of
6-Chloro-2-{4-cyano-4-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidine-1-car-
bonyl}-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester. LC/MS [M+H].sup.+: 560.0. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 7.95 (s, H), 7.48 (m, 2H), 7.22 (t,
2H, J=8.64 Hz, 8.60 Hz), 6.69 (m, H), 6.24 (m, H), 5.47 (d, H,
J=15.28), 5.29 (m, H), 4.59 (m, H), 4.43 (m, H), 4.17 (m, H), 3.79
(s, 3H), 2.89 (s, 2H), 2.73 (s, 2H), 2.22 (m, H), 1.73 (m, H), 1.46
(s, 9H).
Step-4:
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl-
)-4-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidine-4-carbonitrile
[0852] To a solution of
6-Chloro-2-{4-cyano-4-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidine-1-car-
bonyl}-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester (130 mg, 0.23 mmol) in DCM was added trifluoro
acetic acid (0.18 ml,2.32 mmol) dropwise in cold condition. The
mixture was allowed to stir at room temperature 2 hours. Then DCM
was evaporated and the crude mass was diluted with water and washed
with 50% ether-hexane. The aqueous part was basified with 2N NaOH
solution and extracted with ethyl acetate. Ethyl acetate extract
was washed with water and brine, then dried over Na.sub.2SO.sub.4.
Concentration of the organic extract under vacuum afforded 100 mg
(93%) of
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-[(4--
fluoro-phenyl)-hydroxy-methyl]-piperidine-4-carbonitrile. LC/MS
[M+H].sup.+: 460.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.49 (s, H), 7.22 (t, 2H, J=8.72 Hz), 6.59 (m, 2H), 6.21 (m,
H), 5.57 (s, H), 4.97 (m, H), 4.57(s, H), 4.38(m, H), 4.15 (m,H),
3.71 (s, 3H) 3.32 (m, H), 3.20 (m, H), 2.67 (m, 2H), 2.18 (m,H),
1.72 (m, H), 1.54 (m, H)1.29 (m,H). HPLC: 91.6%.
Example 96
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-3-
-(4-fluoro-benzyl)-pyrrolidine-3-carbonitrile
##STR00128##
[0853]
6-Chloro-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarbox-
ylic acid 4-tert-butyl ester was prepared by a process as described
in example 51. Step 1:
3-Cyano-3-(4-fluoro-benzyl)-pyrrolidine-1-carboxylic acid
tert-butyl ester
[0854] Potassium tert. butoxide (137 mg, 1.22 mmol) was added to a
cold stirring solution of 3-Cyano-pyrrolidine-1-carboxylic acid
tert-butyl ester (200 mg, 1.02 mmol) in THF and the resulting
mixture was stirred for an hour. Then
1-Bromomethyl-4-fluoro-benzene (0.13 ml, 1.02 ml, 1 eqv) was added
dropwise at 0.degree. C. The temperature of reaction mixture was
allowed to rise and the mixture was stirred at room temperature
overnight. Then the reaction mass was quenched with ice-water and
was stirred for 10 minutes. THF layer was separated and the aqueous
part was extracted with ethyl acetate. Combined organic layers were
washed with water and brine, dried over Na.sub.2SO.sub.4 and
concentrated. Purification of the crude by column chromatography
(Si-gel, 10% ethyl acetate in hexane) afforded 65 mg of
3-Cyano-3-(4-fluoro-benzyl)-pyrrolidine-1-carboxylic acid
tert-butyl ester. LC/MS [M+H].sup.+: 305.0. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 7.35 (m, 2H), 7.20 (m, 2H), 3.56 (m,
1H), 3.47 (m, 1H), 3.31 (m, 2H), 3.02 (m, 2H), 2.13 (bs, 2H), 1.40
(s, 9H).
Step 2: 3-(4-Fluoro-benzyl)-pyrrolidine-3-carbonitrile
[0855] To a solution of
3-Cyano-3-(4-fluoro-benzyl)-pyrrolidine-1-carboxylic acid
tert-butyl ester (65 mg) in 5 ml of DCM was added trifluoro acetic
acid (0.3 ml) dropwise in cold condition. The mixture was allowed
to stir at room temperature for 2 hours. Then DCM was evaporated
and the crude mass was diluted with water and basified with 2N NaOH
solution and extracted with ethyl acetate. Ethyl acetate extract
was washed with water and brine, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to afford 35 mg of
3-(4-Fluoro-benzyl)-pyrrolidine-3-carbonitrile. LC/MS [M+H].sup.+:
205.3.
Step3:
6-Chloro-2-[3-cyano-3-(4-fluoro-benzyl)-pyrrolidine-1-carbonyl]-7--
dimethylamino-2,3 dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester
[0856] To a solution of
6-Chloro-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (50 mg, 0.14 mmol) in DMF was added EDCI
(35 mg, 0.18 mmol), HOBT (9.5 mg, 0.07 mmol) and DIPEA (0.07 ml
0.42 mmol) at 5.degree. C. The resulting mixture was allowed to
stir at room temperature for 30 minutes and was added a solution of
3-(4-Fluoro-benzyl)-pyrrolidine-3-carbonitrile (28.6 mg, 0.14 mmol)
in DMF. The reaction mixture was allowed to stir at room
temperature overnight. The reaction mass was diluted with
ice-water, stirred for 10 minutes and extracted with ethyl acetate.
Ethyl acetate layer was washed with water and brine, then dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Purification of the crude by column chromatography (Si-gel, 1%
MeOH--DCM) afforded 32 mg (42%) of
6-Chloro-2-[3-cyano-3-(4-fluoro-benzyl)-pyrrolidine-1-carbonyl]-7-dimethy-
lamino-2,3 dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester. LC/MS [M+H].sup.+: 543.4.
Step-4:
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-ca-
rbonyl)-3-(4-fluoro-benzyl)-pyrrolidine-3-carbonitrile
[0857] To a solution of
6-Chloro-2-[3-cyano-3-(4-fluoro-benzyl)-pyrrolidine-1-carbonyl]-7-dimethy-
lamino-2,3 dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester (30 mg, 0.05 mmol) in DCM was added trifluoro acetic acid
(0.04 ml, 0.55 mmol) dropwise in cold condition. The mixture was
allowed to stir at room temperature for 2 hours. Then DCM was
evaporated and the crude mass was diluted with water and basified
with 2N NaOH solution and extracted with ethyl acetate. The organic
layer was washed with water and brine, dried over Na.sub.2SO.sub.4
and concentrated under reduced pressure. Purification of the crude
by column chromatography (Si-gel, 1% MeOH--DCM) afforded 18 mg
(75%) of
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
3-(4-fluoro-benzyl)-pyrrolidine-3-carbonitrile. LC/MS [M+H].sup.+:
443.1. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.36 (m,
2H), 7.20 (m, 2H), 6.61 (s, 2H), 5.77 (m, 1H), 4.79 (bs, 1H), 4.11
(m, 1H), 3.85 (m, 1H), 3.68 (m, 2H), 3.47 (m, 2H), 3.06 (m, 2H),
2.58 (s, 6H), 2.27 (m, 2H). HPLC: 96.2%.
Example 97
{6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dihydr-
o-2H-benzo[1,4]oxazin-7-yl-methyl-cyanamide
##STR00129##
[0858]
7-Amino-6-chloro-2-[((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona--
5,7-dienyl)-methyl-carbamoyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester was prepared as described in example 51.
Step-1:
6-Chloro-7-cyanoamino-2-[((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5-
,7-dienyl)-
methyl-carbamoyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester
[0859] To a solution of
7-Amino-6-chloro-2-[((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5,7-di-
enyl)-methyl-carbamoyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester (100 mg, 0.18 mmol) in diethyl ether was
added cyanogen bromide (100 mg, 0.94 mmol). The reaction mixture
was stirred at room temperature for 2 days. The precipitated solid
was filtered off and mother liquor was concentrated. The organic
crude was purified over column chromatography (Si-gel, 30% ethyl
acetate in hexane) to afford 25 mg (23.7%) of
6-Chloro-7-cyanoamino-2-[((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5-
,7-dienyl)-methyl-carbamoyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester. LC/MS [M+H].sup.+:554.4.
Step-2:
6-Chloro-2-[((5Z7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5,7-die-
nyl)-methyl-carbamoyl]-7-(cyano-methyl-amino)-2,3-dihydro-benzo[1,4]oxazin-
e-4-carboxylic acid tert-butyl ester
[0860] To a solution of
6-Chloro-7-cyanoamino-2-[((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5-
,7-dienyl)-methyl-carbamoyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester (25 mg, 0.04 mmol) in DMF was added anhd.
K.sub.2CO.sub.3 (12 mg, 0.09 mmol) and CH.sub.3I (0.001 ml, 0.09
mmol). The reaction mixture was heated at 40.degree. C. for 3 h.
The reaction mixture was diluted with water and extracted with
ethyl acetate, washed the organic layer with water, brine and dried
over Na.sub.2SO.sub.4. Concentration of organic layer under reduced
pressure afforded 25 mg (100%) of
(6-Chloro-2-[((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5,7-
-dienyl)-methyl-carbamoyl]-7-(cyano-methyl-amino)-2,3-dihydro-benzo[1,4]ox-
azine-4-carboxylic acid tert-butyl ester. LC/MS [M+H].sup.+:
568.6.
Step-3:
6-Chloro-7-(cyano-methyl-amino)-3,4-dihydro-2H-benzo[1,4]oxazine--
2-carboxylic acid
((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5,7-dienyl)-methyl-amide
[0861] To a solution of
6-Chloro-2-[((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5,7-dienyl)-me-
thyl-carbamoyl]-7-(cyano-methyl-amino)-2,3-dihydro-benzo[1,4]oxazine-4-car-
boxylic acid tert-butyl ester. (25 mg, 0.04 mmol) in DCM was added
trifluoroacetic acid (0.3 ml, 3.9 mmol). The reaction mixture was
stirred for about 5 h then concentrated and washed with dry ether.
The resulting TFA salt was diluted with a minimum volume of water
and neutralized with aq. NaOH solution at 5-10.degree. C.
Extraction of the neutralized solution with ethyl acetate followed
by concentration afforded 6 mg (30%) of
6-Chloro-7-(cyano-methyl-amino)-3,4-dihydro-2H-benzo[1,4]oxazine-2-car-
boxylic acid
((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5,7-dienyl)-methyl-amide.
LC/MS [M+H].sup.+: 468.4.
Example 98
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-[difl-
uoro-(4-fluoro-phenyl)-methyl]-piperidine-4-carbonitrile
##STR00130## ##STR00131##
[0862] Step-1:
4-Cyano-4-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic
acid tert-butyl ester
[0863] To a stirred solution of DIPA (0.8 ml, 5.71 m.mol) in THF,
n-BuLi (1.57M) (4.24 ml, 6.66 m.moll) was added to it drop wise in
ice-cold condition. The reaction mixture was stirred for 1 hour and
was added 4-Cyano-piperidine-1-carboxylic acid tert-butyl ester (1
g, 4.76 m.mol) at -78.degree. C. The reaction mixture was stirred
for another 2 hours at room temperature and added
4-Fluoro-benzaldehyde (0.54 ml, 4.76 m.mol,) and stirred the
reaction mixture for 3 h at room temperature, quenched the reaction
mixture with saturated NH.sub.4Cl solution and extracted with ethyl
acetate. The organic layer was washed with water, brine, dried over
Na.sub.2SO.sub.4 and concentrated the solvent under reduced
pressure. Thus obtained crude was purified over column
chromatography (Si-gel, 12% ethyl acetate-hexane) to afford 1.0 g
(52.5%) of
4-Cyano-4-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic
acid tert-butyl ester. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
(ppm): 7.43(m, 2H), 7.1(m, 2H), 4.51(d, 1H), 4.12(m, 3H)), 2.99(m,
3H), 2.32(d, 1H), 2.25(d, 2H), 1.44(s, 9H). LC/MS [M+H].sup.+:
335.3.
Step-2: 4-Cyano-4-(4-fluoro-benzoyl)-piperidine-1-carboxylic acid
tert-butyl ester
[0864] To a stirred solution of
4-Cyano-4-[(4-fluoro-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic
acid tert-butyl ester (200 mg, 0.6 mmol) in ethyl acetate, IBX (335
mg, 1.2 mmol) was added. The reaction mixture was refluxed for 5 h
and filtered through celite bed. The solution was concentrated
under reduced pressure to afford 180 mg (92.3%) of
4-Cyano-4-(4-fluoro-benzoyl)-piperidine-1-carboxylic acid
tert-butyl ester. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm):
8.2 (m, 2H), 7.18 (m, 2H), 4.19 (m, 2H), 3.23 (m, 2H), 2.17-1.2 (m,
4H), 1.46 (s, 9H). LC/MS [M+H].sup.+: 233.4.
Step-3:
4-Cyano-4-[difluoro-(4-fluoro-phenyl)-methyl]-piperidine-1-carbox-
ylic acid tert-butyl ester
[0865] To a solution of
4-Cyano-4-(4-fluoro-benzoyl)-piperidine-1-carboxylic acid
tert-butyl ester (180 mg, 0.54 mmol) in DCM, DAST (2.2 ml, 18.4
mmol) was added. The reaction mixture was stirred for 2 h at room
temperature. The reaction mixture was diluted with water and
organic layer was separated. The organic layer was washed with
water and concentrated under reduced pressure to afford 190 mg
(99.3%) of
4-Cyano-4-[difluoro-(4-fluoro-phenyl)-methyl]-piperidine-1-carboxylic
acid tert-butyl ester. GCMS (m/z):354.
Step-4:
4-[Difluoro-(4-fluoro-phenyl)-methyl]-piperidine-4-carbonitrile
[0866] To a solution of
4-Cyano-4-[difluoro-(4-fluoro-phenyl)-methyl]-piperidine-1-carboxylic
acid tert-butyl ester (190 mg, 0.54 mmol) in DCM was added
trifluoroacetic acid (0.41 ml, 5.4 mmol). The reaction mixture was
stirred for about 5 h then concentrated and washed with dry ether.
The resulting TFA salt was diluted with a minimum volume of water
and neutralized with aq. NaOH solution at 5-10.degree. C.
Extraction of the neutralized solution with ethyl acetate followed
by concentration afforded 130 mg (94.7%) of
4-[Difluoro-(4-fluoro-phenyl)-methyl]-piperidine-4-carbonitrile.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 7.53(m, 2H),
7.17(m, 2H), 3.15(d, 2H), 2.9(t, 2H), 1.89-1.77(m, 4H), 1.25(s,
1H). GCMS(m/z): 254.
Step-5:
6-Chloro-2-{4-cyano-4-[difluoro-(4-fluoro-phenyl)-methyl]-piperid-
ine-1-carbonyl}-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester
[0867] To a stirred solution of
6-Chloro-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (81 mg, 0.236 mmol) in DMF was added DIPEA
(0.12 ml, 0.71 mmol), EDCI (90 mg, 0.47 mmol) and HOBT (48 mg, 0.35
mmol) at 0.degree. C. The reaction mixture was stirred for 1 h at
room temperature and was added
4-[Difluoro-(4-fluoro-phenyl)-methyl]-piperidine-4-carbonitrile (60
mg, 0.24 mmol). The reaction mixture was stirred for overnightand
diluted with water. The precipitated solid was filtered and dried
to afford 130 mg (95.8%) of
6-Chloro-2-{4-cyano-4-[difluoro-(4-fluoro-phenyl)-methyl]-piperidine-1-ca-
rbonyl}-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm):
7.56-6.46(m, 6H), 4.87-4.17(m, 4H), 3.83(s, 3H), 3.72-3.38(m, 3H),
2.86(m, 1H), 2.03-1.82(m, 3H), 1.54(s, 9H). LC/MS [M+H].sup.+:
580.4.
Step-6:
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl-
)-4-[difluoro-(4-fluoro-phenyl)-methyl]-piperidine-4-carbonitrile
[0868] To a stirred solution of
6-Chloro-2-{4-cyano-4-[difluoro-(4-fluoro-phenyl)-methyl]-piperidine-1-ca-
rbonyl}-7-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester (130 mg, 0.23 mmol) in DCM, TFA (0.17 ml, 2.25
mmol) was added in ice-cold condition. The reaction mixture was
stireed for 2 h at room temperature and, concentrared the reaction
mixture, diluted with water, basified the compound with NaHCO.sub.3
solution and extracted with ethyl acetate. The organic layer was
wased with water, brine, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to afford 50 mg (45.3%) of
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-[dif-
luoro-(4-fluoro-phenyl)-methyl]-piperidine-4-carbonitrile. LC/MS
[M+H].sup.+: 480.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.64-6.55(m, 6H), 5.58(s, 1H), 5.0-4.19(m, 3H), 3.7(s, 3H),
3.21(m, 2H), 1.99-1.34(m, 6H). HPLC: 97.6%
Example 99
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-[difluoro-(4-fluoro-phenyl)-methyl]-piperidine-4-carbonitrile
##STR00132##
[0869]
4-[Difluoro-(4-fluoro-phenyl)-methyl]-piperidine-4-carbonitrile was
prepared by a process as described in example 98. Step-1:
6-Chloro-2-{4-cyano-4-[difluoro-(4-fluoro-phenyl)-methyl]-piperidine-1-ca-
rbonyl}-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester
[0870] To a stirred solution of
6-Chloro-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (180 mg, 0.236 m.mol) in DMF was added
DIPEA (0.12 ml, 0.708 m.mol), EDCI (90 mg, 0.472 m.mol) and HOBT
(48 mg, 0.354 m.mol) were added at 0.degree. C. The reaction
mixture was stirred for lh at room temperature and added
4-[Difluoro-(4-fluoro-phenyl)-methyl]-piperidine-4-carbonitrile (60
mg, 0.236 m.mol. The reaction mixture was stirred for overnight and
diluted with water. The precipitated solid was filtered and dried
to afford 110 mg (79.2%) of
6-Chloro-2-{4-cyano-4-[difluoro-(4-fluoro-phenyl)-methyl]-piperidine-1-ca-
rbonyl}-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester. LC/MS [M+H].sup.+: 593.4. .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. (ppm): 7.54-6.56 (m, 6H), 4.84-2.84 (m,
6H), 2.75 (s, 6H), 2.34-1.82 (m, 5H), 1.52 (s, 9H).
Step-2:
(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-{-
4-[difluoro-(4-fluoro-phenyl)-methyl]-piperidin-1-yl}-methanone
[0871] To a solution of
6-Chloro-2-{4-cyano-4-[difluoro-(4-fluoro-phenyl)-methyl]-piperidine-1-ca-
rbonyl}-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester (110 mg, 0.19 mmol) in DCM was added
trifluoroacetic acid (0.14 ml, 1.86 mmol). The reaction mixture was
stirred for about 5 h then concentrated and washed with dry ether.
The resulting TFA salt was diluted with a minimum volume of water
and neutralized with aq. NaOH solution at 5-10.degree. C.
Extraction of the neutralized solution with ethyl acetate followed
by concentration afforded 35 mg (37.4%) of
(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-{4-[diflu-
oro-(4-fluoro-phenyl)-methyl]-piperidin-1-yl}-methanone. LC/MS
[M+H].sup.+:493.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.63-6.54 (m, 6H), 5.74 (s, 1H), 5.0-4.2 (m, 3H), 3.2 (m,
2H), 2.67 (s, 1H), 2.56-2.5 (d, 6H), 1.99-1.34 (m, 5H).
HPLC-93.02%.
Example 100
1-[6-Chloro-7-(1H-pyrazol-4-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbony-
l]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00133##
[0872]
1-(7-Bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4--
(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared by a
process described in example 57. Step-1:
(6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-(1-trit-
yl-1H-pyrazol-4-yl)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester)
[0873] A solution of
7-Bromo-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (100
mg, 0.1687 mmol) and
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-trityl-1H-pyrazole
in tolune-water (1:1) and was degassed for one hour. To that
solution were added sodium carbonate (36 mg, 0.3374 mmol) and
catalytic amount of Pd(dppf).sub.2Cl.sub.2 (10 mole %). The
reaction mixture was refluxed for 12 hours and diluted with water.
The organics was extracted with ethyl acetate, dried over sodium
sulfate and concentrated under reduced pressure to get the crude
mass. Purification of that crude mass by flash chromatography
(Si-gel, 15% ethyl acetate-hexane) afforded 105 mg (81%) of
(6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-(1-t-
rityl-1H-pyrazol-4-yl)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester). .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 8.10 (s, 1H), 8.04 (s, 1H), 7.58-7.10 (m, 21H), 5.43 (s,
1H), 4.33 (m, 1H), 4.11 (bs, 2H), 3.65 (m, 1H), 3.14 (m, 2H), 2.92
(m, 2H), 2.50 (m, 2H), 1.82 (m, 2H), 1.46 (m, 9H).
Step-2:
(1-[6-Chloro-7-(1H-pyrazol-4-yl)-3,4-dihydro2H-benzo[1,4]oxazine--
2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile)
[0874] To a solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-(1-trity-
l-1H-pyrazol-4-yl)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester (100 mg, 0.12 mmol) was added trifluoro acetic
acid (0.09 ml, 1.22 mmol) and the reaction mixture was stirred for
16 hours. The reaction mixture was concentrated under reduced
pressure and diluted with water, neutralized with 1(N) NaOH
solution and extracted with ethyl acetate. The organic layer was
dried over sodium sulfate and concentrated to afford 25 mg (42%) of
(1-[6-Chloro-7-(1H-pyrazol-4-yl)-3,4-dihydro2H-benzo[1,4]oxazine-2-carbon-
yl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile). LC/MS
[M+H].sup.+: 480.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 12.85 (bs, 1H), 7.85 (bs, 2H), 7.33 (bs, 2H), 7.18 (m, 2H),
6.92 (m, 1H), 6.67 (s, 1H), 6.15 (s, 1H), 4.97 (s, 1H), 4.40 (m,
1H), 4.11 (m, 1H), 3.40 (m, 2H), 3.10 (m, 2H), 3.07 (s, 1H), 2.68
(m, 1H), 1.81 (m, 2H), 1.54(m, 1H). HPLC: 98.8%.
Example 101
6-Chloro-7-[methyl-(2H-tetrazol-5-yl)-amino]-3,4-dihydro-2H-benzo[1,4]oxaz-
ine-2-carboxylic acid
[3-cyano-3-(4-fluoro-benzyl)-pentyl]-methyl-amide
##STR00134##
[0875] Step-1:
6-Chloro-7-cyanoamino-2-[((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5-
,7-dienyl)-methyl-carbamoyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester
[0876]
7-Amino-6-chloro-2-R(5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5-
,7-dienyl)-methyl-carbamoyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester (100 mg, 0.18 mmol) was taken in diethyl
ether, added cyanogen bromide (100 mg, 0.94 mmol) and stirred at
room temperature for two days. The reaction mixture was filtered,
concentrated and purified over flash chromatography (Si-gel, 30%
ethyl acetate-hexane) to afford 25 mg (22.2%) of
6-Chloro-7-cyanoamino-2-[((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5-
,7-dienyl)-methyl-carbamoyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester. LC/MS [M+H].sup.+:554.4.
Step-2 :
6-Chloro-2-[((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5,7-d-
ienyl)-methyl-carbamoyl]-7-(cyano-methyl-amino)-2,3-dihydro-benzo[1,4]oxaz-
ine-4-carboxylic acid tert-butyl ester
[0877] To a solution of
6-Chloro-7-cyanoamino-2-[((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5-
,7-dienyl)-methyl-carbamoyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester (25 mg, 0.04 mmol) in DMF was added anhd.
K.sub.2CO.sub.3(12 mg, 0.09 mmol) and CH.sub.3I (13 mg. 0.0005 ml,
0.09 mmol). The reaction mixture was heated at 40.degree. C. for 3
h., diluted with ice-water, extracted with ethyl acetate, washed
with waterand concentrated to afford 25 mg (100%) of
6-Chloro-2-[((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5,7-dienyl)-me-
thyl-carbamoyl]-7-(cyano-methyl-amino)-2,3-dihydro-benzo[1,4]oxazine-4-car-
boxylic acid tert-butyl ester. LC/MS [M+H].sup.+: 568.6
Step-3:
6-Chloro-2-[((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5,7-di-
enyl)-methyl-carbamoyl]-7-[methyl-(2H-tetrazol-5-yl)-amino]-2,3-dihydro-be-
nzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
[0878] To a solution of
6-Chloro-2-[((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5,7-dienyl)-me-
thyl-carbamoyl]-7-(cyano-methyl-amino)-2,3-dihydro-benzo[1,4]oxazine-4-car-
boxylic acid tert-butyl ester (190 mg, 0.34 mmol) in DMF was added
sodium azide (87 mg, 1.3 mmol) and ammonium chloride (72 mg, 1.3
mmol). The reaction mixture was heated at 100.degree. C. overnight.
The reaction mixture was diluted with water and precipitated solid
was filtered. The solid was washed with water and dried to afford
110 mg (50.3%) of
6-Chloro-2-[((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5,7-dienyl)-me-
thyl-carbamoyl]-7-[methyl-(2H-tetrazol-5-yl)-amino]-2,3-dihydro-benzo[1,4]-
oxazine-4-carboxylic acid tert-butyl ester. LC/MS [M+H].sup.+:
611.2
Step-4:
6-Chloro-7-[methyl-(2H-tetrazol-5-yl)-amino]-3,4-dihydro-2H-benzo-
[1,4]oxazine-2-carboxylic acid
((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5,7-dienyl)-methyl-amide
[0879] To a solution of
6-Chloro-2-[((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5,7-dienyl)-me-
thyl-carbamoyl]-7-[methyl-(2H-tetrazol-5-yl)-amino]-2,3-dihydro-benzo[1,4]-
oxazine-4-carboxylic acid tert-butyl ester (110 mg, 0.18 mmol)) in
DCM was added trifluoroacetic acid (1.14 ml, 1.8 mmol). The
reaction mixture was stirred for about 5 h then concentrated and
washed with dry ether. The resulting TFA salt was diluted with a
minimum volume of water and neutralized with aq. NaOH solution at
5-10.degree. C. Extraction of the neutralized solution with ethyl
acetate followed by concentration afforded 20 mg (20.4%) of
(6-Chloro-7-[methyl-(2H-tetrazol-5-yl)-amino]-3,4-dihydro-2H-benzo[1,4]ox-
azine-2-carboxylic acid
((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5,7-dienyl)-methyl-amide.
LC/MS [M+H].sup.+: 511.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 7.35-6.68 (m, 6 H), 6.34 (bs, 1H), 5.80 (m, 1H),
4.94 (m, 2H), 4.40 (m, 1H), 4.10 (m, 1H), 3.41-1.72 (m, 12 H), HPLC
purity: 89.6%.
Example 102
1-[6-Chloro-7-(2H-tetrazol-5-ylamino)-3,4-dihydro-2H-benzo[1,4]oxazine-2-c-
arbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00135##
[0880]
6-Chloro-7-cyanoamino-2-[((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl--
nona-5,7-dienyl)-methyl-carbamoyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxy-
lic acid tert-butyl ester was prepared by a process as described in
example 101. Step-1:
6-Chloro-2-N5Z7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5,7-dienyl)-methy-
l-carbamoyl]-7-(5H-tetrazol-5-ylamino)-2,3-dihydro-benzo[1,4]oxazine-4-car-
boxylic acid tert-butyl ester
[0881] To a solution of
6-Chloro-7-cyanoamino-2-R(5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5,-
7-dienyl)-methyl-carbamoyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester (150 mg, 0.27 mmol) in DMF was added sodium
azide (70 mg, 1.1 mmol) and ammonium chloride (58 mg, 1.08 mmol).
The reaction mixture was heated at 100.degree. C. overnight. The
reaction mixture was diluted with water and precipitated solid was
filtered. The solid was washed with water and dried to afford 70 mg
(44.4%) of
6-Chloro-2-[((5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5,7-dienyl)-me-
thyl-carbamoyl]-7-(5H-tetrazol-5-ylamino)-2,3-dihydro-benzo[1,4]oxazine-4--
carboxylic acid tert-butyl ester. LC/MS [M+H].sup.+: 597.4.
Step-2:
1-[6-Chloro-7-(2H-tetrazol-5-ylamino)-3,4-dihydro-2H-benzo[1,4]ox-
azine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0882] To a stirred solution of
6-Chloro-2-R(5Z,7E)-3-cyano-3-ethyl-8-fluoro-5-vinyl-nona-5,7-dienyl)-met-
hyl-carbamoyl]-7-(5H-tetrazol-5-ylamino)-2,3-dihydro-benzo[1,4]oxazine-4-c-
arboxylic acid tert-butyl ester (70 mg, 0.12 mmol) in DCM was added
TFA (1.1 ml, 14.3 mmol) at 0.degree. C. and stirred at room
temperature for 2 h. The reaction mixture was concentrated and
diluted with water, basified with NaOH solution, extracted with
ethyl acetate. The organic layer was concentrated and purified
through flash chromatography (Si-gel, 1% MeOH-DCM) to afford 10 mg
(16.8%). LC/MS [M+H].sup.+: 497.4.HPLC: 72.3%.
Example 103
1-[6-Chloro-7-dimethylamino-4-(2,2,2-trifluoro-acetyl)-3,4-dihydro-2H-benz-
o[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00136##
[0883]
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared by
a process described in example 51.
[0884] To a solution of
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile (100 mg, 0.438 mmol)
in DCM was added tri ethyl amine (0.09 ml, 0.657 mmol) and tri
fluoro acetic acid anhydride (0.07 ml, 0.5694) drop wise in ice
cold condition. The reaction mixture was stirred for 3 hour at room
temperature. The reaction mixture was diluted with water and
stirred for half of an hour. Then the organic layer was separated,
washed with brine, dried over sodium sulfate and concentrated under
reduced pressure to get the crude mass which was then purified over
column chromatography (Si-gel, 10% ethyl acetate in hexane) to
afford 35 mg (14%) of
1-[6-Chloro-7-dimethylamino-4-(2,2,2-trifluoro-acetyl)-3,4-dihydro-2H-ben-
zo[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile.
LC/MS [M+H].sup.+: 553.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 7.85 (d, 1H), 7.34 (d, 2H), 7.20 (m, 2H), 6.71 (m,
1H), 4.35 (m, 1H), 4.15 (m, 1H), 3.99 (s, 2H), 3.17-1.52 (14H).
HPLC: 92.1%.
Example 104
1-[6-Chloro-7-methoxy-4-(2,2,2-trifluoro-acetyl)-3,4-dihydro-2H-benzo[1,4]-
oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00137##
[0886] To a stirred solution of
1-(6-Chloro-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-f-
luoro-benzyl)-piperidine-4-carbonitrile (0.100g, 0.225 m.mol) in
DCM was added TEA (0.094 ml, 0.675 m.mol) and trifluoro acetic
anhydride (0.04 ml, 0.293 m.mol) drop wise in ice-cold condition.
The reaction mixture was stirred for 4 h at room temperature.
Concentrated thereaction mixture under reduced pressure and diluted
with water. The organics was extracted with ethyl acetate, washed
with water, brine, dried over Na.sub.2SO4 and concentrated the
solvent under reduced pressure. Thus obtained crude was purified
with column chromatography (Si-gel, 17% ethyl acetate-hexane)to
afford 57 mg (45.9%) of
1-[6-Chloro-7-methoxy-4-(2,2,2-trifluoro-acetyl)-3,4-dihydro-2H-benzo[1,4-
]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile.
.sup.1H NMR-(CR783-3506-34 in DMSO-d.sub.6)-7.88(d, 1H),
7.37-7.17(m, 4H), 6.8(d, 1H), 5.62(m, 1H), 4.37-4.0(m, 4H), 3.86(d,
3H), 2.96-2.67(m, 3H), 1.9-1.5(m, 5H). LCMS (M+H)-540.2.
HPLC-95.77%
Example 105
1-(6-Chloro-7-methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00138##
[0888] To a solution of
6-Chloro-7-methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid (150 mg, 0.58 mmol) in DMF was added
4-(4-Fluoro-benzyl)-piperidine-4-carbonitrile (127 mg, 0.58 mmol),
EDCI (168 mg, 0.87 mmol), HOBt (95 mg, 07 mmol) and DIPEA (0.31 ml,
1.75 mmol) at 5-10.degree. C. The reaction mixture was stirred at
room temperature for 15 hours then diluted with water and extracted
with ethyl acetate. The ethyl acetate layer was concentrated in
vacuo and subjected to column chromatography (Si-gel, 20%
EtOAC-hexane) to afford 120 mg (45.1%) of
1-(6-Chloro-7-methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LCMS (M+H): 458.2.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 10.8 (m, 1H),
7.36 (m, 2H), 7.20 (m, 2H), 7.16 (m, 2H), 5.87 (m, 1H), 4.32 (m,
2H), 3.80 (m, 3H), 3.21-1.70 (m, 8H). HPLC-96.3%.
Example 106
1-(6-Chloro-7-imidazol-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00139##
[0889]
7-Bromo-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbon-
yl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester was prepared by a process as described in example 57. Step-1:
1-(6-Chloro-7-imidazol-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0890] To a solution of
7-Bromo-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (100
mg, 0.17 mmol) in DMF was added imidazole (14 mg, 0.2 mmol) and
cesium carbonate (116 mg, 0.35 mmol). The solution was degassed
with argon during 1 hour. To the previous degassed solution was
added copper iodide (4 mg, 0.02 mmol) followed by
N,N-dimethylethylenediamine (6 mg, 0.07 mmol) and was heated at
170.degree. C. overnight. The reaction mixture was passed through a
celite bed was diluted with water. The organics was extracted with
ethyl acetate. The organic layer was concentrated and purified over
column chromatography (Si-gel, 1% MeOH-DCM) to afford 12 mg (16.2%)
of
1-(6-Chloro-7-imidazol-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
480.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.72 (bs,
1H0, 7.32-6.70 (m, 8H), 6.49 (s, 1H), 5.05 (m, 1H), 4.38 (m, 1H),
4.08 (m, 1H), 2.93 (m, 3H0, 1.90 (m, 4H), 1.77 (m, 3H). HPLC
purity: 93.8%.
Example 107
1-[6-Chloro-7-methoxy-4-(2H-tetrazol-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazin-
e-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00140##
[0891]
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-me-
thoxy-2,3-dihydro-benzo[1,4]oxazine-4-carbonitrile was prepared by
a process as described in example 81.
[0892] To a solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-methoxy--
2,3-dihydro-benzo[1,4]oxazine-4-carbonitrile in DMF was added
NaN.sub.3 (44 mg, 0.682 mmol) and NH.sub.4Cl (36 mg, 0.682 mmol)
and heated in a sealed tube at 120.degree. C. for 16 hours. Then
the reaction mixture was diluted with water, extracted ethyl
acetate, washed with brine, dried over sodium sulfate and
concentrated under reduced pressure followed by washing with hexane
to afford 25 mg (28%) of
1-[6-Chloro-7-methoxy-4-(2H-tetrazol-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazi-
ne-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS
[M+H].sup.+: 512.5. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 8.02 (m, 1H), 7.33 (bs, 2H), 7.19 (bs, 2H), 6.78 (m, 1H),
5.73 (s, 1H), 4.15 (m, 4H), 3.81 (s, 3H), 2.93 (m, 2H), 2.66 (m,
1H), 1.80 (m, 3H), 1.60 (m, 1H), 1.28(m, 1H). HPLC: 96%.
Example 108
4-(4-Fluoro-benzyl)-1-(quinoxaline-2-carbonyl)-piperidine-4-carbonitrile
##STR00141##
[0894] To a stirred solution of Quinoxaline-2-carboxylic acid (100
mg, 0.57 mmol) in DMF was added DIPEA (0.3 ml, 0.72 mmol), EDCI
(220 mg, 1.15 mmol), and HOBT (116 mg, 0.86 mmol) at 0.degree. C.
The reaction mixture was stirred for half an hour atroom
temperature and was added
4-(4-Fluoro-benzyl)-piperidine-4-carbonitrile (125 mg, 0.57 mmol).
The reaction mixture was stirred overnight atroom temperature,
diluted with water and extracted with ethyl acetate. The organic
layer was washed with water, brine, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. Thus obtained crude was
purified with column chromatography (Si-gel, 0.5% MeOH-DCM) to
afford 110 mg (51.4%) of
4-(4-Fluoro-benzyl)-1-(quinoxaline-2-carbonyl)-piperidine-4-carbonitrile.
LC/MS [M+H].sup.+: 375.4. .sup.1.sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 9.1 (s, 1H), 8.17-7.94 (m, 4H), 7.36 (t, 2H), 7.17
(t, 2H), 4.64 (d, 1H), 4.0 (d, 1H), 3.27 (m, 1H), 2.99 (m, 3H),
1.93 (m, 1H), 1.79 (m, 3H). HPLC: 97.1%
Example 109
4-(4-Fluoro-benzyl)-1-([1,2,4]triazolo[1,5-a]pyrimidine-2-carbonyl)-piperi-
dine-4-carbonitrile
##STR00142##
[0895]
4-(4-Fluoro-benzyl)-1-([1,2,4]triazolo[1,5-a]pyrimidine-2-carbonyl)-
-piperidine-4-carbonitrile was prepared by a process similar to
that described in example 108.
[0896] LC/MS [M+H].sup.+: 365.2. .sup.1.sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 9.46 (m, 1H), 8.96 (m, 1H), 7.47 (m,
1H), 7.35 (m, 2H), 7.18 (m, 2H), 4.59 (d, 1H), 4.05 (d, 1H), 3.17
(m, 1H), 2.95 (m, 3H), 1.94 (m, 1H), 1.73 (m, 3H). HPLC: 99.6%
Example 110
4-(4-Fluoro-benzyl)-1-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-piperidine-4--
carbonitrile
##STR00143##
[0897]
4-(4-Fluoro-benzyl)-1-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-piperi-
dine-4-carbonitrile was prepared by a process similar to that
described in example 108. LCMS (M+H)-364.4. .sup.1H
NMR-(CR783-3506-56 in DMSO-d.sub.6)-9.22(d, 2H), 8.71(d, 1H),
8.42(s, 1H), 7.37-7.16(m, 5H), 4.5(m, 2H), 4.0(m, 2H), 2.96(s, 2H),
1.81-1.74(m, 4H). HPLC-99.88%.
Example 111
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,3-dihydro-
-benzo[1,4]oxazine-4-carbonitrile
##STR00144##
[0899] To a stirred solution of
1-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fluoro-benz-
yl)-piperidine-4-carbonitrile) (330 mg, 0.797 mmol) in DMF were
added K.sub.2CO.sub.3 (330 mg, 2.39 mmol) and cyanogens bromide
(126 mg, 1.19 mmol) in ice cool condition. The reaction mixture was
stirred for 16 hours at room temperature and then it was diluted
with water, extracted with ethyl acetate, washed with brine, dried
over sodium sulfate and concentrated under resduced pressure to get
the crude mass which was then purified by silica gel column
chromatography (Si-gel, 20% ethyl acetate in hexane) to afford 160
mg (46%) of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,3-dihydr-
o-benzo[1,4]oxazine-4-carbonitrile. LC/MS [M+H].sup.+: 439.2.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.34 (m, 2H),
7.19 (m, 2H), 7.01 (m, 3H), 5.37 (s, 1H), 4.35 (m, 1H), 4.12 (m,
1H), 3.98 (m, 2H), 3.22-1.47 (8H). HPLC: 94.2%
Example 112
1-[6-Chloro-4-(2H-tetrazol-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbon-
yl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00145##
[0900]
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,3--
dihydro-benzo[1,4]oxazine-4-carbonitrile was prepared by a process
as described in example 111.
[0901] To a solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,3-dihydr-
o-benzo[1,4]oxazine-4-carbonitrile (50 mg, 0.114 mmol) in DMF were
added NH.sub.4Cl (24 mg, 0.455 mmol) and NaN.sub.3 (30 mg, 0.455
mmol). The reaction mixture was taken in a sealed tube and it was
heated at 120.degree. C. for 16 hours. Then it was diluted with
water and extracted with water. The organic layer was separated and
washed wth brine, dried over sodium sulfate and concentrated under
reduced pressure to give the crude product which was washed with
hexane to afford 15 mg (27%) of
1-[6-Chloro-4-(2H-tetrazol-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbo-
nyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS
[M+H].sup.+: 482.3. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 8.36 (m, 1H), 7.30 (m, 2H), 7.16 (m, 2H), 6.86 (d, 1H), 6.77
(bs, 1H), 5.20 (m, 1H), 4.32 (m, 1H), 4.13 (m, 2H), 3.86 (m, 1H),
3.10-1.44 (8H). HPLC: 92.3%.
Example 113
1-[6-Chloro-4-(1H-[1,2,4]triazol-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2--
carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00146##
[0902]
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,3--
dihydro-benzo[1,4]oxazine-4-carbonitrile was prepared by a process
as described in example 111.
[0903] To a stirred solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,3-dihydr-
o-benzo[1,4]oxazine-4-carbonitrile (90 mg, 0.21 mmol) in n-butanol
(7 ml) were added NH.sub.2NHCHO (16 mg, 0.27 mmol) and
K.sub.2CO.sub.3 (56 mg, 0.41 mmol) in ice cool condition. Then the
reaction mixture was refluxed for 16 hours. The reaction mixtures
was concentrated and then diluted with ethyl acetate and water. The
organic layer was separated, washed with brine, dried over sodium
sulfate and concentrated under reduced pressure to afford the crude
mass which was then purified by column chromatography (Si-gel, 5%
methanol--DCM) to afford 20 mg (20%) of
1-[6-Chloro-4-(1H-[1,2,4]triazol-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-
-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS
[M+H].sup.+: 479.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 13.64 (s, 1H), 8.42 (m, 1H), 7.34 (bs, 2H), 7.19 (m, 2H),
6.89 (m, 2H), 5.25 (m, 1H), 4.36-3.96 (m, 4H), 3.20-1.38 (m, 8H).
HPLC: 96.1%.
Example 114
1-(6-Chloro-7-pyrrol-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(-
4-fluoro-benzyl) piperidine-4-carbonitrile
##STR00147##
[0904]
7-Bromo-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbon-
yl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester was prepared by a process as described in example 57.
[0905] To a solution of
7-Bromo-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (200
mg, 0.34 mmol) in DMF was added Pyrrole (26 mg, 0.38 mmol) in a
sealed tube. The reaction mixture was degassed with Argon for about
15 min followed by addition of cesium carbonate (231 mg, 0.71
mmol), copper iodide (13 mg, 0.07 mmol) and N,N dimethyl
ethylenediammine (12 mg, 0.135 mmol). The reaction mixture was
heated at 170.degree. C. overnight. The reaction mixture was
filtered through celite bed and purified over column chromatography
(Si-gel, 1.5% MeOH-DCM) to afford 26 mg (16%) of
1-(6-Chloro-7-pyrrol-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4--
(4-fluoro-benzyl) piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
479.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.33 (2H,
bs), 7.19(2H, bs), 6.83 (3H, m), 6.37 (3H, bs), 5.02 (1H, bs), 4.38
(1H, bs), 4.09 (1H, bs), 3.44 (1H,m), 3.34 (2H, s), 2.93 (2H, m),
2.68 (1H, m), 1.85 (3H, m), 1.77 (1H, m). HPLC purity: 91.1%.
Example 115
1-[6-Chloro-7-methoxy-4-(1H-[1,2,4]triazol-3-yl)-3,4-dihydro-2H-benzo[1,4]-
oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00148##
[0906]
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-me-
thoxy-2,3-dihydro-benzo[1,4]oxazine-4-carbonitrile was prepared as
described in example 81.
[0907] To a stirred solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-methoxy--
2,3-dihydro-benzo[1,4]oxazine-4-carbonitrile)(100 mg, 0.21 mmol) in
n-butanol (7 ml) were added NH.sub.2NHCHO (16 mg, 0.27 mmol) and
K.sub.2CO.sub.3(59 mg, 0.426 mmol) in ice cool condition. Then the
reaction mixture was subjected to reflux for 16 hours. Then the
reaction mixture was concentrated and then diluted with ethyl
acetate and water. Organic layer was separated, washed with brine,
dried over sodium sulfate and concentrated under reduced pressure
to give the crude mass which was then purified by silica gel column
chromatography (5% methanol-DCM) to afford 10 mg (10%) of
1-[6-Chloro-7-methoxy-4-(1H-[1,2,4]triazol-3-yl)-3,4-dihydro-2H-benzo[1,4-
]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile.
LC/MS [M+H].sup.+: 511.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 13.51 (s, 1H), 8.35 (m, 1H), 7.34 (bs, 2H), 7.21(m,
2H), 6.71(m, 1H), 6.44 (m, 1H), 5.26 (m, 1H), 4.36 (m, 1H), 4.15
(m, 2H), 3.79 (s, 3H), 3.19-1.39 (m, 8H). HPLC: 75.2%.
Example 116
1-[6-Chloro-8-(1H-pyrazol-4-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbony-
l]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00149## ##STR00150##
[0908] Step-1: 2-Bromo-4-chloro-6-nitro-phenol
[0909] To a solution of 4-chloro-2-nitrophenol (1 g, 5.76 mmol) in
acetic acid was added bromine (0.32 ml, 6.3 mmol) at 5-10.degree.
C. and stirred at 10.degree. C. for half an hour. The temperature
of the reaction mixture was raised to room temperature and stireed
at RT for 3 hours. The reaction mixture was diluted with ice-water
and extracted with ethyl acetate. The organic layer was washed with
ethyl acetate and dried over sodium sulfate. Concentration of
organic layer was afforded 1.3 g (90.9%) of
2-Bromo-4-chloro-6-nitro-phenol. GCMS [m/z]: 253.0. .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta. (ppm): 11.1 (s, 1H), 8.10 (d, 1H),
8.04 (d, 1H).
Step-2: 2-Amino-6-bromo-4-chloro-phenol
[0910] To a solution of 2-bromo-4-chloro-6-nitro-phenol (2.7 g,
10.6 mmol) in ethyl acetate was added raney Ni (1 g) and was
hydrogenetaed at ballon pressure for 4 hours. The reaction mixture
was filtered through celite bed and mother liquor was concentrated
to afford 2 g (85.1%) of 2-Amino-6-bromo-4-chloro-phenol. LCMS
[M+1]: 224.0. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm):
6.67 (s, 1H), 6.61 (s, 1H), 6.57 (s, 1H), 5.2 (bs, 2H).
Step-3:
8-Bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
ethyl ester
[0911] 2-Amino-6-bromo-4-chloro-phenol (360 mg, 1.62 mmol) was
dissolved in acetone. Anhydrous K.sub.2CO.sub.3 (603.7 mg, 4.37
mmol) and diethyl-2-bromomalonate (0.25 ml, 1.8 mmol) were added to
the solution and the resulting mixture was refluxed overnight. The
reaction mixture was concentrated, diluted with ice-water and
extracted with ethyl acetate. The organic layer was washed
successively with water and brine and then dried over
Na.sub.2SO.sub.4. The organic layer was concentrated under reduced
pressure and purification of the residue by flash chromatography
(silica-gel, 5% EtOAc-hexane) afforded 270 mg (52.1%) of
8-Bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
ethyl ester. LCMS [M+1]: 322.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 6.81 (d, 1H), 6.59 (d, 1H), 6.45 (s, 1H), 5.14 (t,
1H), 4.01 (q, 2H), 3.49 (m, 1H), 3.47 (d, 1H), 1.16 (t, 3H).
Step-4:
8-Bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester
[0912] DMAP (57 mg, 4.6 mmol) and (Boc).sub.2O (1 ml, 5.0 mmol)
were added to a solution of
8-Bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
ethyl ester (1.5 g, 4.6 mmol) in THF and the resulting mixture was
heated to reflux overnight. The mixture was then concentrated,
diluted with water and extracted with ethyl acetate. The organic
layer was dried over sodium sulfate and concentrated under reduced
pressure. The crude product was purified through column
chromatography over Si-gel (6%-ethyl acetate-hexane) to afford 1.2
g (63.1%) of
8-Bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 7.76 (s, 1H), 7.47 (s, 1H), 5.38 (s,
1H), 4.51 (d, 1H), 4.11 (m, 2H), 3.57 (d, 1H), 1.45 (s, 9H), 1.20
(t, 3H).
Step-5:
8-Bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester
[0913] To a solution of
8-Bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester (1 gm, 2.4 mmol) in (4:1)
THF: H2O was added (110 mg, 2.6 mmol) LiOH. The reaction mixture
was stirred at room tempearture for 3 hours. The reaction mixture
was concentrated, diluted with water, neutralized with acetic acid
and extracted with ethyl acetate. The organic layer was washed with
water and concentrated under reduced pressure to afford 920 mg
(98.9%) of
8-Bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 13.5 (brs, 1H), 7.72 (s, 1H), 7.44 (s, 1H), 5.23 (s,
1H), 4.48 (m, 1H), 3.54 (m, 1H), 1.39 (s, 9H).
Step-6:
8-Bromo-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carb-
onyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tent-butyl
ester
[0914] To a solution of
8-Bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (1.1 gm, 2.8 mmol) in DMF was added DIPEA
(1.6 ml, 8.4 mmol) at cold condition followed by addition of EDCI
(805 mg, 4.2 mmol) and HOBT (380 mg, 2.8 mmol). The reacting
solution was stirred for 30 minutes and was added
4-(4-Fluoro-benzyl)-piperidine-4-carbonitrile (615 mg, 2.8 mmol).
The reaction mixture was stirred at room temperature overnight. The
reaction mixture was diluted with water and extracted with ethyl
acetate. The organic layer was washed with water, concentrated and
purified over column chromatography (Si-gel, 15% ethyl
acetate-hexane) to afford 1.3 g (78.3%) of
8-Bromo-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.69-7.17 (m,
6H), 5.57 (m, 1H), 4.36-1.43 (m, 21H).
Step-7:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-8--
(1-trityl-1H-pyrazol-4-yl)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester
[0915] To a solution of
8-Bromo-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (100
mg, 0.17 mmol) in 3:1 toluene-water was added
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-trityl-1H-pyrazole
(74 mg, 0.17 mmol) and Na.sub.2CO.sub.3 (36 mg, 0.34 mmol). The
solution was degassed with nitrogen for 1 hour and was added
catalytic amount of Pd(dppf).sub.2Cl.sub.2 at argon atmosphere. The
reaction mixture was heated at 90.degree. C. for overnight, diluted
with water and extracted with ethyl acetate. The organic layer was
washed with water, brine and dried over Na.sub.2SO.sub.4. The
organics was concentrated and purified purified over column
chromatography (Si-gel, 15% ethyl acetate-hexane) to afford 110 mg
(78.7%) of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-8-(1-trity-
l-1H-pyrazol-4-yl)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 8.15-7.05 (m, 23H), 5.45-1.79 (m, 13H), 1.43 (s, 9H).
Step-8
[0916] To a solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-8-(1-trity-
l-1H-pyrazol-4-yl)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester (100 mg, 0.12 mmol) in DCM was added TFA (2 ml)
and stirred at RT for 4 hours. The DCM solution was concentrated,
diluted with water and basified with dilute NaOH solution. The
organics was extracted with ethyl acetate, washed with water. The
organic layer was concentrated and purified over column
chromatography (Si-gel, 1% MeOH-DCM) to afford 55 mg (95.5%) of
1-[6-Chloro-8-(1H-pyrazol-4-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbon-
yl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS
[M+H].sup.+: 480.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 12.93 (m, 1H), 8.13-6.19 (m, 9H), 4.94 (m, 1H), 4.42 (m,
1H), 3.96 (m, 1H), 3.47-1.54 (m, 10H). HPLC: 95.2%.
Example 117
1-(6-Chloro-8-pyridin-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4--
(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00151##
[0917]
8-Bromo-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbon-
yl]-2,3-dihydro-benzo[1, 4]oxazine-4-carboxylic acid tert-butyl
ester was prepared by a process as described in example 116.
Step-1:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-8-pyridin--
4-yl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester
[0918] To a solution of
8-Bromo-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (100
mg, 0.17 mmol) in 3:1 toluene-water was added pyridine-4-boronic
acid (21 mg, 0.17 mmol), Na.sub.2CO.sub.3 (36 mg, 0.34 mmol). The
solution was degassed with nitrogen for 1 hour and was added
catalytic amount of Pd(dppf).sub.2Cl.sub.2 at argon atmosphere. The
reaction mixture was heated at 90.degree. C. for overnight, diluted
with water and extracted with ethyl acetate. The organic layer was
washed with water, brine and dried over Na.sub.2SO.sub.4. The
organics was concentrated and purified purified over column
chromatography (Si-gel, 1.5% MeOH-DCM) to afford 70 mg (69.7%) of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-8-pyridin--
4-yl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester. LCMS [M+H].sup.+: 491.2.
Step-2
[0919] To a solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-8-pyridin--
4-yl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester (70 mg, 0.11 mmol) in DCM was added TFA (1 ml) and stirred at
RT for 3 hours. The DCM solution was concentrated, diluted with
water and basified with dilute NaOH solution. The organics was
extracted with ethyl acetate, washed with water. The organic layer
was concentrated and washed with hexane to afford 30 mg (55.5%) of
1-(6-Chloro-8-pyridin-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
491.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 8.60 (m,
2H), 7.52 (d, 2H), 7.32-7.19 (m, 4H), 6.68-6.41(m, 3H), 5.01 (m,
1H), 4.37 (m, 1H), 3.84 (m, 1H), 3.41 (m, 2H), 3.02-1.18 (m, 814).
HPLC: 98.8%
Example 118
1-(6-Chloro-8-thiophen-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00152##
[0920]
8-Bromo-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbon-
yl]-2,3-dihydro-benzo[1, 4]oxazine-4-carboxylic acid tert-butyl
ester was prepared by a process as described in example 116.
[0921]
1-(6-Chloro-8-thiophen-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared by
a similar process i.e Suzuki coupling with thiophene-3-boronic acid
followed by deprotection as described in example 117.
[0922] LC/MS [M+H].sup.+: 496.4. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 7.78 (m, 1H), 7.61 (m, 1H), 7.45 (d,
1H), 7.30 (m, 2H), 7.19 (m, 2H), 6.74 (m, 1H), 6.57 (m, 1H), 6.30
(m, 1H), 4.97 (m, 1H), 4.41 (m, 1H), 3.93 (m, 1H), 3.34 (m, 2H),
2.95 (m, 3H), 2.66(m, 2H), 1.900.93 (m, 3H).
[0923] HPLC:89.5%.
Example 119
1-(6-Chloro-7-thiophen-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00153##
[0924]
1-(7-Bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4--
(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared by a
process described in example 57. Step-1:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-thiophen-
-3-yl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tent-butyl
ester
[0925] To a stirred solution of
7-Bromo-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
(0.17 m.mol, 0.100 g) Na.sub.2CO.sub.3 (0.36 m.mol, 0.036 g) and
Thiophene boronic acid (0.17 m.mol, 0.022 g) in toluene: water
(3:1, degassed with Ar) were further degassed with Ar for 1 h, then
[Pd(dppf).sub.2Cl.sub.2] (25 mg) was added to it and heated the
reaction mixture at 100.degree. C. for overnight. Water was added
to it. Extracted the compound with ethyl acetate, washed with
water, brine, dried over Na.sub.2SO4 and concentrated the solvent
under reduced pressure. Thus obtained crude was purified with
column chromatography using 100-200 mesh silica gel, 15% EA/Hex as
Eluent to get (0.085g) of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-thiophen-
-3-yl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester (6). LCMS (M+H)-496.2.
[0926] .sup.1H NMR-(CR783-3506-72 in CDCl.sub.3)-7.99-6.93(m, 6H),
4.93-3.35(m, 7H), 2.87(s, 2H), 2.03-1.66(m, 4H), 1.55(s, 9H).
Step-2:
1-(6-Chloro-7-thiophen-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-ca-
rbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0927] To a stirred solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-thiophen-
-3-yl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester. (0.143 m.mol, 0.085 g) in DCM (10 ml), TFA (1.43 m.mol, 0.11
ml) was added in ice-cold condition. Left the reaction mixture for
2 h at rt.concentrared the reaction mixture and diluted with water,
basified the compound with dil NaOH solution Extracted the compound
with Ethyl acetate, washed with water, brine, dried over
Na.sub.2SO4 and concentrated the solvent under reduced pressure,
washed the compound with Hexane to get (0.030 g) of
1-(6-Chloro-7-thiophen-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
496.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.56 (m,
2M), 7.33 (m, 2H), 7.20 (m, 1H), 7.16 (m, 2H), 6.87 (m, 1H), 6.69
(s, 1H), 6.29 (s, 2H), 4.97 (m, 1H), 4.38 (m, 1H), 4.10 (m, 1H),
3.32 (m, 2H), 3.07 (m, 1H), 2.94 (s, 2H), 1.90 (m, 4H), 1.51 (m,
1H). HPLC: 94.1%.
Example 120
1-(6-Chloro-7-pyridin-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4--
(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00154##
[0928] Step-1:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-pyridin--
3-yl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tent-butyl
ester
[0929] To a stirred solution of
7-Bromo-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
(0.17 m.mol, 0.100 g) Na.sub.2CO.sub.3 (0.36 m.mol, 0.036 g) and
Pyridine boronic acid (0.17 m.mol, 0.021 g) in toluene: water (3:1,
degassed with Ar) were further degassed with Ar for 1 h, then
Pd(dppf).sub.2Cl.sub.2 (25 mg) was added to it and heated the
reaction mixture at 100.degree. C. for overnight. Water was added
to it. Extracted the compound with ethyl acetate, washed with
water, brine, dried over Na.sub.2SO4 and concentrated the solvent
under reduced pressure. Thus obtained crude was purified with
column chromatography using 100-200 mesh silica gel, 25% EA/Hex as
Eluent to get (0.067 g) of of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-pyridin--
3-yl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester (6). .sup.1H NMR-(CR783-3506-74 in CDCl.sub.3)-8.66-6.85(m,
10H), 4.97-3.39(m, 7H), 2.87(s, 2H), 2.09-1.64(m, 4H), 1.55(s, 9H).
LCMS (M+H)-591.2.
Step-2:
1-(6-Chloro-7-pyridin-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-car-
bonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0930] To a stirred solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-pyridin--
3-yl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester (0.11 m.mol, 0.067 g) in DCM (10 ml), TFA (1.1 m.mol, 0.085
ml) was added in ice-cold condition. Left the reaction mixture for
2 h at rt.concentrared the reaction mixture and diluted with water,
basified the compound with dil NaOH solution Extracted the compound
with Ethyl acetate, washed with water, brine, dried over
Na.sub.2SO4 and concentrated the solvent under reduced pressure,
washed the compound with Hexane to get (0.014 g) of
1-(6-Chloro-7-pyridin-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
491.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm):
8.57-6.76(m, 10H), 6.41(s, 1H), 4.39-2.67(m, 8H), 1.86-1.54(m, 5H).
HPLC purity: 94.7%.
Example 121
1-(6-Chloro-7-pyridin-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4--
(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00155##
[0932]
1-(6-Chloro-7-pyridin-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbo-
nyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared by
the similar procedure as described in example 120. LC/MS
[M+H].sup.+: 491.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 8.58 (bs, 2H), 7.41 (m, 2H), 7.33 (m, 2H), 7.17 (m, 2H0,
6.87 (m, 1H), 6.74 (m, 1H), 6.49 (bs, 1H), 5.01 (m, 1H) 4.39 (m,
1H), 4.07 (m, 1H), 3.32 (m, 2H, 3.15 (m, 1H) 2.93 (bs, 3H), 2.69
(m, 2H), 1.83 (m, 2H). HPLC purity: 94.5%.
Example 122
1-[6-Chloro-7-(2-methyl-2H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine--
2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00156##
[0933]
1-[6-Chloro-7-(2-methyl-2H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[1,4]o-
xazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
was prepared by similar process as described in example 120. LC/MS
[M+H].sup.+: 494.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.43 (bs, 1H), 7.33 (m, 2H), 7.18 (m, 2H), 6.75 (m, 2H),
6.49 (bs, 1H), 6.21 (bs, 1H), 5.00 (bs, 1H), 4.39 (m, 1H), 3.62 (s,
3H), 3.44 (m, 1H), 3.11 (m, 1H), 2.93 (s, 2H), 1.71 (m, 4H). HPLC
purity: 88.5%.
Example 123
1-[6-Chloro-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-benzo[1,4]oxazine--
2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00157##
[0934]
1-[6-Chloro-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-benzo[1,4]o-
xazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
was prepared by similar process as described in example 120. LC/MS
[M+H].sup.+: 494.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.94-6.16(m, 9H), 4.97(m, 1H), 4.39(m, 1H), 4.09(m, 1H),
3.85(s, 3H), 3.41-1.55(m, 10H). HPLC purity: 87.1%.
Example 124
Laevo and dextro enantiomers of
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4fluoro-benzyl)-piperidine-4-carbonitrile
Preparation of two epimers of
6-Chloro-7-dimethylamino-2-(2-hydroxy-1-phenyl-ethylcarbamoyl)-2,3-dihydr-
o-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
##STR00158##
[0935]
Racemic-6-Chloro-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4--
dicarboxylic acid 4-tert-butyl ester was prepared as described in
example 51.
[0936] To a solution of
6-Chloro-7-dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (13.5 g, 0.038 mol) in DCM was added
(S)-(+)-phenylglycinol (5.19 g, 0.038 mmol), EDCI (9.46 g, 0.049
mol), HOBt (2.56 g, 0.019 mol) and DIPEA (19.3 ml, 0.12 mol) at
5-10.degree. C. The reaction mixture was stirred at room
temperature for 15 hours then diluted with water and extracted with
DCM. The organic layer was concentrated in vacuo and subjected to
column chromatography (Si-gel, 25-35% ethyl acetate-hexane) to
afford epimer-I (4.5 g , 24.9%) and epimer-II (.about.4 g) of
6-Chloro-7-dimethylamino-2-(2-hydroxy-1-phenyl-ethylcarbamoyl)-2,3-dihydr-
o-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester. LC/MS
[M+H].sup.+: 476.4
Example 124a
Laevo-isomer of
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00159##
[0937] Step-1
[0938] Epimer- I of
6-Chloro-7-dimethylamino-2-(2-hydroxy-1-phenyl-ethylcarbamoyl)-2,3-dihydr-
o-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
([.alpha.]=-2.7.degree.; c 1.03% in CHCl.sub.3) 4.4 g, was
dissolved in dioxane-water (1:1) and was added 3 (N)
H.sub.2SO.sub.4 (50 ml) dropwise. The solution was refluxed for 5-6
hours and pH was adjusted to 8-9. The organics were extracted with
ethyl acetate and 10% EtOH-ethyl acetate. The organic layer was
washed with brine solution and dried over Na.sub.2SO.sub.4. The
organic layer was concentrated to afford 1.5 g (63.5%) of the
dextro-enantiomer of
6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid. LC/MS [M+H].sup.+: 257.1. [.alpha.]=+38.degree.; c 0.094% in
MeOH
Step-2
[0939] The dextro-enantiomer of
6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ([.alpha.]=+38.degree.; c 0.094% in MeOH) (1.4 g, 5.45 mmol)
in dichloromethane were added EDCI (1.35 g, 7.08 mmol), HOBt (370
mg, 2.72 mmol), DIPEA (3 ml, 16.3 mmol) and
4-(4-Fluoro-benzyl)-piperidine-4-carbonitrile (1.55 g, 5.45 mmol)
at 5.degree. C. The reaction mixture was stirred at room
temperature for 20 hours. The reaction mixture was diluted with
water and extracted with dichloromethane. The organic layer was
washed successively with water, brine and dried over
Na.sub.2SO.sub.4 The organic solution was concentrated and purified
over column chromatography (Si-gel, 35% ethyl acetate-hexane) to
afford 1.1 g (44.8%) of laevo enantiomer of
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
457.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.34 (bs,
2H), 7.20 (m, 2H), 6.58 (m, 2H), 5.74 (bs, 1H), 4.94 (m, 1H), 4.37
(m, 1H), 4.09 (m, 1H), 3.22 (m, 2H), 2.95 (m, 2H), 2.70 (m, 1H),
2.49 (s, 6H), 1.81 (m, 4H), 1.54 (m, 1H).
[0940] Chiral HPLC: 99.4%; ee 98.7%. [.alpha.]=-46.1.degree.; c
0.97% in CHCl.sub.3.
Example 124b
Dextro-isomer of
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00160##
[0941] Step-1
[0942] Epimer-II of
6-Chloro-7-dimethylamino-2-(2-hydroxy-1-phenyl-ethylcarbamoyl)-2,3-dihydr-
o-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (isolated in
step-1) 500 mg, was dissolved in dioxane-water (1:1) and was added
3(N) H.sub.2SO.sub.4 50 ml dropwise. The solution was refluxed for
5-6 hours and pH was adjusted to 8-9. The organics was extracted
with ethyl acetate and 10% EtOH-ethyl acetate. The organic layer
was washed with brine solution and dried over Na.sub.2SO.sub.4. The
organic layer was concentrated to afford 352 mg of laevo- isomer of
6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid.
[0943] LC/MS [M+H].sup.+: 257.1.
Step-2
[0944] The laevo-isomer of
6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid (350 mg, 1.36 mmol) in dichloromethane were added EDCI (339.3
mg, 1.77 mmol), HOBt (91.9 mg, 0.68 mmol), DIPEA (0.7 ml, 4.1 mmol)
and 4-(4-Fluoro-benzyl)-piperidine-4-carbonitrile (386.3 mg, 1.7
mmol) at 5.degree. C. The reaction mixture was stirred at room
temperature for 20 hours. The reaction mixture was diluted with
water and extracted with dichloromethane. The organic layer was
washed with water, brine solution and dried over Na.sub.2SO.sub.4
The organic solution was concentrated and purified over column
chromatography (Si-gel, 35% ethyl acetate-hexane) to afford 62 mg
(10%) of the dextro enantiomer of
1-(6-Chloro-7-dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
457.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.34 (bs,
2H), 7.20 (m, 2H), 6.58 (m, 2H), 5.74 (bs, 1H), 4.94 (m, 1H), 4.37
(m, 1H), 4.09 (m, 1H), 3.22 (m, 2H), 2.95 (m, 2H), 2.70 (m, 1H),
2.49 (s, 6H), 1.81 (m, 4H), 1.54 (m, 1H). Chiral HPLC: 100%;
ee=100%. [.alpha.]=+50.1.degree.; c 0.63% in CHCl.sub.3.
Example 125
1-(6-Chloro-7-pyrazol-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4--
(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00161##
[0946] To a solution of
7-Amino-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (250
mg, 0.47 mmol) in aqueous HCl (5 ml) was added aqueous NaNO.sub.2
solution (64.9 mg, 0.94 mmol) at -5.degree. C. and small amount of
1,4-dioxane was added to dissolve the compound completely and then
stirred at 5-10.degree. C. for 2 hour. Then
SnCl.sub.2.2H.sub.2O(446 mg, 2.35 mmol) in concentrated HCl was
added and colour of the reaction mass became off white from light
yellow with precipitation. The reaction mixture was stirred at
10.degree. C. for 1 hour. The solid was filtered and subjected to
forward reaction without purification. To a solution of the crude
mass of
1-(6-Chloro-7-hydrazino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrilein ethanol (5 ml) was
added tetramethoxy propane (0.1 ml, 0.61 mmol) and refluxed for 1
hour. A yellow solid was precipitated on cooling. The yellow solid
was filtered, washed with cold ethanol. To that added water,
basified with 1(N) NaOH solution, extracted with ethyl acetate,
washed with water, brine, dried over Na.sub.2SO.sub.4 and then
concentrated. The organic mass was purified over column
chromatography (silica gel, 0.8% methanol-DCM) to afford 20 mg
(8.9%) of
1-(6-Chloro-7-pyrazol-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
480.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 9.36 (m,
1H), 8.21 (m, 1H), 7.67 (m, 1H), 7.33 (m, 2H), 7.19 (m, 2H), 7.02
(m, 2H), 5.64 (m, 1H), 5.35 (m, 1H), 4.32-1.74 (m, 11H). HPLC
purity: 84.8%.
Example 126
1-(6-Chloro-7-pyrimidin-5-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00162##
[0947]
1-(6-Chloro-7-pyrimidin-5-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-car-
bonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared
by similar process as described in example 120. LC/MS [M+H].sup.+:
492.4. LCMS purity: 90.7%.
Example 127
1-(6-Chloro-7-hexa deuterio
dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fluoro-be-
nzyl)-piperidine-4-carbonitrile
##STR00163##
[0948]
7-Amino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester was prepared by a process
similar to that described in example 51. Step-1: 6-Chloro-7-hexa
deuterio
dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic acid
4-tert-butyl ester 2-ethyl ester
[0949]
7-Amino-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester (400 mg, 1.12 mmol) was
dissolved in DMF. Then to it K.sub.2CO.sub.3 (464 mg, 3.36 mmol)
and CD.sub.3I (0.21 ml, 3.36 mmol) were added at cold condition. It
was then heated at 40.degree. C.-45.degree. C. for overnight. Then
it was diluted with water and extracted with ethyl acetate. Organic
layer was washed with water and brine. It was dried and
concentrated to produce 6-Chloro-7-hexa deuterio
dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic acid
4-tert-butyl ester 2-ethyl ester (250 mg, 57.1%).
[0950] LCMS: 391.2.
Step-2:6-Chloro-7-hexa deuterio
dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic acid
4-tert-butyl ester
[0951] 6-Chloro-7-hexa deuterio
dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic acid
4-tert-butyl ester 2-ethyl ester (250 mg, 0.64 mmol) was dissolved
in (4:1) THF: water and to it LiOH (55 mg, 1.3 mmol) was added at
cold condition. It was stirred at RT for 3 hours. Then it was
concentrated and neutralized by 50% aq. glacial acetic acid. It was
extracted with ethyl acetate and organic layer was washed with
water, brine. It was dried, concentrated and washed with hexane to
produce 6-Chloro-7-hexa deuterio
dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic acid
4-tert-butyl ester (180 mg, 77.5%). LCMS: 363.4.
Step-3:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7--
hexa
deuteriodimethylamino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester
[0952] 6-Chloro-7-hexa deuterio
dimethylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic acid
4-tert-butyl ester (180 mg, 0.49 mmol) was dissolved in dry DMF and
to it DIPEA (0.3 ml, 1.48 mmol) was added drop wise at cold
condition. EDCI (143 mg, 0.74 mmol), HOBT (108 mg, 0.49 mmol) were
then added to the reaction mixture and stirred for 0.5 hour.
4-(4-Fluoro-benzyl)-piperidine-4-carbonitrile (109 mg, 0.49 mmol)
was then added to the reaction mixture and stirred overnight. It
was then diluted with water and extracted with ethyl acetate.
Organic layer was washed with water and brine. Finally it was
dried, concentrated and purified through column chromatography
using (10-30%) EA/hexane in SiO.sub.2 to produce
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-hexa
deuteriodimethylamino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester (185 mg, 67.04%). LCMS: 563.2.
Step-4: 1-(6-Chloro-7-hexa deuterio
dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fluoro-be-
nzyl)-piperidine-4-carbonitrile
[0953]
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-he-
xa deuteriodimethylamino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester (180 mg, 0.32 mmol) was dissolved in DCM. TFA
(0.25 ml, 3.2 mmol) was added to the reaction mixture at cold
condition. It was then stirred at RT for 1 hour and concentrated.
It was diluted with water and basified. After that it was extracted
with ethyl acetate. Organic layer was washed with water, brine and
dried. It was concentrated and washed with hexane to produce
1-(6-Chloro-7-hexa deuterio
dimethylamino-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fluoro-be-
nzyl)-piperidine-4-carbonitrile (140 mg, 94.5%). LC/MS [M+H].sup.+:
463.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.34(brs,
2H), 7.19(m, 2H), 6.58(m, 2H), 5.75(s, 1H), 4.96-1.23(m, 13H).
[0954] HPLC purity: 92.6%
Example 128
1-(6-Chloro-7-furan-2-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-
-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00164##
[0955]
1-(6-Chloro-7-furan-2-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbony-
l)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared by
similar process as described in example 120. LC/MS [M+H].sup.+:
480.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm):
7.71-6.44(m, 10H), 5.00(m, 1H), 4.39(m, 1H), 4.11(m, 1H),
3.40-1.53(m, 10H). HPLC purity: 91.2%.
Example 129
1-(6-Chloro-7-furan-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-
-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00165##
[0956]
1-(6-Chloro-7-furan-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbony-
l)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared by
similar process as described in example 120. LC/MS [M+H].sup.+:
480.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.94 (s,
1H), 7.70 (m, 1H), 7.35 (m, 2H), 7.19 (m, 2H), 6.90 (m, 1H), 6.78
(m, 1H), 6.68 (s, 1H), 6.27 (bs, 1H), 4.99 (m, 1H), 4.41 (m, 1H0,
4.10 (m, 1H), 3.40 (m, 1H), 2.95 (bs, 2H), 2.68 (m, 1H), 1.81 (m,
4H), 1.54 (m, 2H). HPLC purity: 90.1%.
Example 130
1-[6-Chloro-7-(4-methyl-imidazol-1-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2--
carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00166##
[0957]
1-[6-Chloro-7-(4-methyl-imidazol-1-yl)-3,4-dihydro-2H-benzo[1,4]oxa-
zine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was
prepared by a process similar to that described in example 106.
LC/MS [M+H].sup.+: 494.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 7.57 (bs, 1H), 7.33 (m, 2H), 7.18 (m, 2H), 6.95 (m,
1H), 6.85 (m, 1H), 6.75 (bs, 1H), 6.46 (bs, 1H), 5.03 (m, 1H), 4.38
(m, 1H), 3.45 (m, 1H), 3.18 (m, 1H), 2.93 (s, 3H), 2.73 (m, 2H),
2.13 (s, 3H), 1.90 (m, 2H), 1.74 (m, 2H). HPLC purity: 95.5%.
Example 131
1-[6-Chloro-7-(3-methyl-pyrazol-1-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-c-
arbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00167##
[0958]
1-[6-Chloro-7-(3-methyl-pyrazol-1-yl)-3,4-dihydro-2H-benzo[1,4]oxaz-
ine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was
prepared by a process similar to that described in example 106.
LC/MS [M+H].sup.+: 494.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 7.75 (bs, 1H), 7.34 (m, 2H), 7.19 (m, 2H), 6.86 (m,
1H), 6.72 (bs, 1H), 6.44 (bs, 1H), 6.21 (bs, 1H), 5.03 (m, 1H),
4.39 (m, 1H), 4.10 (m, 1H), 3.43 (m, 2H), 3.17 (m, 1H), 2.94 (s,
3H), 2.69 (m, 2H), 2.21 (s, 3H), 1.83-1.53 (m, 2H). HPLC purity:
92.6%.
Example 132
1-(6-Chloro-7-[1,2,4]triazol-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbo-
nyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00168##
[0959] A mixture of
7-Amino-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (400
mg, 0.67 mmol), Hydrazine hydrate (84 mg, 1.5 mmol) and
triethylamine (3 ml) was refluxed in triethylothoformate at
150.degree. C. overnight fitted with Dean-Stark apparatus. The
triethylorthoformate was ditilled off and the reaction mixture was
diluted with water and extracted with ethyl acetate. The organic
layer was concentrated and purified over column chromatography
(Si-gel, 1% MeoH-DCM) to afford 20 mg (6.1%) of
1-(6-Chloro-7-[1,2,4]triazol-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS
[M+H].sup.+: 481.4. .sup.1H-NMR (400 MHz, DMSO- d.sub.6) .delta.
(ppm): 8.68 (bs, 2H), 7.33 (bs, 2H), 7.18 (m, 2H), 7.05 (m, 1H),
6.79 (bs, 1H), 6.61 (bs, 1H), 5.07 (bs, 1H), 4.38 (bs, 1H),
3.47-1.51 (m, 10H). HPLC purity: 93.0%
Example 133
1-(6-Chloro-7-[1,2,3]triazol-1-yl-3,4-dihydro-2H-benzol[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00169##
[0960] Step-1:
7-Azido-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
[0961] To a solution of
7-Amino-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (200
mg, 0.38 mmol) in acetonitrile was added slowly tert-butyl nitrite
(40.05 ml, 0.42 mmol) followed by TMS azide (0.09 ml, 0.76 mmol)
dropwise at 0.degree. C. The resulting solution was stirred at room
temperature for one hour. The reaction mixture was concentrated and
ourified over column chromatography (Si-gel, 0.2% MEOH-DCM) to
afford 150 mg (71%) of
7-Azido-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester. The
material was used in next step without any characterization. LC/MS
[M+H+NH.sub.3].sup.+: 572.5, 574.3
Step-2:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7--
[1,2,3]triazol-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester
[0962] To a solution of
7-Azido-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (150
mg, 0.27 mmol), potassium carbonate (373.6 mg, 2.7 mmol),
CuSO.sub.4 (13.5 mg, 0.054 mmol), sodium ascorbate (21.4 mg, 0.11
mmol) and trimethylsilylacetylene (0.05 ml, 0.32 mmol) in
methanol-dioxane-water (1:1:1) in sealed tube. The reaction mixture
was heated at 100.degree. C. overnight. The resulting suspension
was extracted with ethyl acetate. The organic layer was washed with
water and dried over sodium sulfate. The organics was purified over
column chromatography (Si-gel, 0.5% MeOH-DCM) to afford 60 mg
(46.2%) of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-[1,2,3]t-
riazol-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester.
[0963] LC/MS [M-FH].sup.+: 581.4.
Step-3:
1-(6-Chloro-7-[1,2,3]triazol-1-yl-3,4-dihydro-2H-benzo[1,4]oxazin-
e-2-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0964] To a solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-[1,2,3]t-
riazol-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester (60 mg, 0.103 mmol)) in DCM was added
trifluoroacetic acid (0.3 ml). The reaction mixture was stirred for
about 5 h then concentrated and washed with dry ether. The
resulting TFA salt was diluted with a minimum volume of water and
neutralized with aq. NaOH solution at 5-10.degree. C. Extraction of
the neutralized solution with ethyl acetate followed by
concentration afforded 30 mg (60.5%) of
1-(6-Chloro-7-[1,2,3]triazol-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS
[M+H].sup.+: 481.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 8.36 (m, 1H), 7.89 (m, 1H), 7.33 (m, 2H), 7.18 (m, 2H), 7.00
(m, 1H), 6.80 (s, 1H), 6.68 (s, 1H), 5.07 (m, 1H), 4.38 (m, 1H),
4.06 (m, 1H), 3.46 (m, 1H), 3.40 (m, 1H), 3.19 (m, 1H), 2.93 (s,
2H), 2.69 (m, 1H), 1.80 (m, 2H), 1.72 (m, 1H), 1.54 (m, 1H). HPLC
purity: 95.5%.
Example 134
1-(6-Chloro-4-methyl-7-oxazol-5-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00170##
[0965] Step-1:
1-(6-Chloro-7-formyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile
[0966] To a dry DMF (0.6 ml0 was added POCl.sub.3 (0.6 ml) and
sirirred the solution for 30 min at room temperature. To the
DMF-POCl.sub.3 solution was added a solution of
1-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fluoro-benz-
yl)-piperidine-4-carbonitrile (880 mg, 2.06 mmol) in 2 ml DMF and
stirred the solution at 60.degree. C. overnight. The Reaction
mixture was diluted with ice and extracted with ethyl acetate. The
organic layer was washed with water and dried over sodium sulfate.
The organic layer was concentrated under redused pressure to afford
750 mg (79.9%) of
1-(6-Chloro-7-formyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
456.0
Step-2:
1-(6-Chloro-4-methyl-7-oxazol-5-yl-3,4-dihydro-2H-benzo[1,4]oxazi-
ne-2-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0967] To a mixture of
1-(6-Chloro-7-formyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile (130 mg, 0.29 mmol) and
sodium methoxe (48.6 mg, 0.9 mmol) in methanol was added
p-Tosylmethylisocyanide (68 mg, 0.35 mmol). The reaction mixture
was refluxed one hour. The reaction mixture was concentrated,
diluted with water and extracted with ethyl acetate. The organic
layer was concentrated to afford 53 mg (36.9%) of
1-(6-Chloro-4-methyl-7-oxazol-5-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2--
carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0968] LC/MS [M+H].sup.+: 495.0. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 8.40 (m, 1H), 7.53 (bs, 1H), 7.34 (bs,
2H), 7.18 (m, 2H), 7.11 (m, 1H), 6.82 (m, 1H), 5.19 (bs, 1H), 4.37
(m, 1H), 4.12 (m, 1H), 3.41 (m, 2H), 3.20 (m, 1H), 2.93 (bs, 4H),
2.67 (m, 1H), 1.91-1.53 (m, 5H). HPLC purity: 90.7%.
Example 135
1-[6-Chloro-7-dimethylamino-4-(1H-[1,2,4]triazol-3-yl)-3,4-dihydro-2H-benz-
o[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00171##
[0969] Preparation of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-dimethyl-
amino-2,3-dihydro-benzo[1,4]oxazine-4-carbonitrile was described in
example 76. Step-1:
1-[6-Chloro-7-dimethylamino-4-(1H-[1,2,4]triazol-3-yl)-3,4-dihydro-2H-ben-
zo[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0970] To a solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-dimethyl-
amino-2,3-dihydro-benzo[1,4]oxazine-4-carbonitrile (100 mg, 0.21
mmol) in n-butanol was added formic hydrazide (16 mg, 0.21 mmol)
and anhd. potassium carbonate (57 mg, 0.41 mmol). The reaction
mixture was heated at 120.degree. C. overnight. The reaction
mixture was concentrated, diluted with water and extracted with
ethyl acetate. The organic layer was washed with water and dried
over sodium sulfate. The organic layer was concentrated and
purified over column chromatography (Si-gel, 1.5% MeOH-DCM) to
afford 9 mg (8%) of
1-[6-Chloro-7-dimethylamino-4-(1H-[1,2,4]triazol-3-yl)-3,4-dihydro-2H-ben-
zo[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile.
LC/MS [M+H].sup.+: 524.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 8.40 (m, 1H), 8.28 (m, 1H), 7.34 (m, 2H), 7.19 (m,
2H), 6.70 (m, 1H), 5.23 (m, 1H), 4.32 (m, 1H), 4.16 (m, 1H), 3.04
(m, 3H), 2.65 (s, 6H), 1.77 (m, 3H), 1.39 (m, 3H), 1.23 (m, 1H).
HPLC purity: 87.0%.
Example 136
1-[6-Chloro-7-(6-fluoro-pyridin-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-c-
arbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00172##
[0971]
1-[6-Chloro-7-(6-fluoro-pyridin-3-yl)-3,4-dihydro-2H-benzo[1,4]oxaz-
ine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrilewas
prepared by similar process as described in example 120.
[0972] LC/MS [M+H].sup.+: 509.4. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 8.20 (bs, 1H), 7.98 (m, 1H), 7.33 (m,
2H), 7.17 (m, 3H), 6.85 (m, 1H), 6.75 (bs, 1H), 6.41 (bs, 1H), 5.00
(bs, 1H), 4.33 (m, 1H), 4.10 (m, 1H), 3.30 (m, 1H), 2.93 (s, 3H),
2.66 (m, 1H), 1.80 (m, 3H). HPLC purity: 92.9.
Example 137
1-[6-Chloro-7-(6-methoxy-pyridin-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2--
carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00173##
[0973]
1-[6-Chloro-7-(6-methoxy-pyridin-3-yl)-3,4-dihydro-2H-benzo[1,4]oxa-
zine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was
prepared by similar process as described in example 120. LC/MS
[M+H].sup.+: 521.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 8.13 (s, 1H), 7.70 (d, 1H), 7.33 (m, 2H), 7.17 (m, 2H), 6.76
(m, 3H), 6.31 (bs, 1H), 4.98 (m, 1H), 4.39 (bs, 1H), 4.03 (m, 1H),
3.87 (s, 3H0, 3.42 (m, 1H), 3.15 (m, 1H), 2.93 (s, 3H), 2.72 (m,
2H), 1.80 (m, 4H). HPLC purity: 93.5%.
Example 138
1-[6-Chloro-7-(2-methoxy-pyridin-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2--
carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00174##
[0974]
1-[6-Chloro-7-(2-methoxy-pyridin-3-yl)-3,4-dihydro-2H-benzo[1,4]oxa-
zine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was
prepared by similar process as described in example 120. LC/MS
[M+H].sup.+: 521.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 8.15 (bs, 1H), 7.51 (bs, 1H), 7.32 (m, 2H), 7.18 (m, 2H),
7.03 (bs, 1H), 6.69 (m, 2H), 6.26 (bs, 1H), 4.97 (bs, 1H), 4.39 (m,
1H), 4.05 (m, 1H), 3.81 (s, 3H), 3.42 (m, 1H), 3.18 (m, 2H), 2.93
(s, 3H), 2.69 (m, 1H), 1.54 (m, 4H). HPLC purity: 93.9%.
Example 139
1-(6-Chloro-7-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00175##
[0975] Step-1:
1-(6-Chloro-7-formyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile
[0976] To a dry DMF (0.6 ml0 was added POCl.sub.3 (0.6 ml) and
sirirred the solution for 30 min at room temperature. To the
DMF-POCl.sub.3 solution was added a solution of
1-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fluoro-benz-
yl)-piperidine-4-carbonitrile (880 mg, 2.06 mmol) in 2 ml DMF and
stirred the solution at 60.degree. C. overnight. The Reaction
mixture was diluted with ice and extracted with ethyl acetate. The
organic layer was washed with water and dried over sodium sulfate.
The organic layer was concentrated under redused pressure to afford
750 mg (79.9%) of
1-(6-Chloro-7-formyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
456.0.
Step-2:
1-(6-Chloro-7-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-ca-
rbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0977] To a solution of
1-(6-Chloro-7-formyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile (100 mg, 0.22 mmol) in
methanol was added sodium borohydride (12 mg, 0.31 mmol) at
0.degree. C. and stirred at 5-10.degree. C. for 2 hours. The
reaction mixture was quenched with ice and stirred for 10 mins. The
reaction mixture aws concentrated and extracted with ethyl acetate.
The organic layer was washed with water and dried over sodium
sulfate. The organic layer was concentrated under redused pressure
and purified over column chromatography (Si-gel, 0.5% MeOH-DCM) to
afford 50 mg (49.6%) of
1-(6-Chloro-7-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)--
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
458.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.34 (bs,
2H), 7.19 (m, 1H), 6.85 (m, 1H), 6.67 (m, 1H), 5.14 (bs, 2H), 4.40
(bs, 2H, 4.12 (m, 1H), 3.23 (m, 3H0, 2.96 (bs, 2H), 2.83 (s, 3H),
2.67 (m, 1H), 1.78 (m, 3H), 1.54 (m, 1H). HPLC purity: 96.4%.
Example 140
1-(6-Chloro-2-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-flu-
oro-benzyl)-piperidine-4-carbonitrile
##STR00176##
[0978] Step-1: 2-Methyl-malonic acid diethyl ester
[0979] Metallic sodium (790 mg, 34.3 mmol) was added to ethanol (70
ml) and stirred at room temperature for 1 hour. Diethyl malonate
(4.8 ml, 31.2 mmol) was added drop wise to the previously prepared
ethanolic solution at ice cold condition and stirred the solution
at room temperature for 1 hour. Methyl iodide (5.9 ml, 93.6 mmol)
was added drop wise to the ethanolic solution. The reaction mixture
was stirred at room temperature overnight. The ethanolic solution
was concentrated, diluted with water and extracted with ethyl
acetate. The organic layer was washed with water, brine and dried
over sodium sulphate. Concentration of the organic layer afforded
3.88 g (71.4%) of 2-Methyl-malonic acid diethyl ester. .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta. (ppm): 4.18 (m, 4H), 3.40 (m, 1H),
1.40 (d, 3H), 1.24 (q, 6H).
Step-2: 2-Bromo-2-methyl-malonic acid diethyl ester
[0980] To a stirred solution of 2-methyl-malonic acid diethyl ester
(3.88 g, 22.3 mmol) in DCM (80 ml) was added a solution of Br.sub.2
(1.14 ml, 22.3 mmol) in DCM (10 ml) drop wise under cold condition
and the reaction mixture was stirred at room temperature for 1
hour. The reaction mixture was concentrated to afford 5.04 g
(89.3%) of 2-bromo-2-methyl-malonic acid diethyl ester. GCMS [m/z]:
253.0
Step-3:
6-Chloro-2-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbox-
ylic acid ethyl ester
[0981] To a solution of 4-chloro-2-amino phenol (100 mg, 0.7 mmol)
in DMF was added anhd. Cs.sub.2CO.sub.3 (570 mg, 1.8 mmol) and
2-bromo-2-methyl-malonic acid diethyl ester (264 mg, 1.04 mmol)
drop wise under cold condition. The reaction mixture was stirred at
room temperature overnight. The reaction mass was diluted with
water, extracted with ethyl acetate, washed with water, brine and
dried over Na.sub.2SO.sub.4. The organic layer was concentrated and
the crude mass was purified by flash chromatography (silica gel,
10% ethlyl acetate-hexane) to afford 120 mg (63.5%) of
6-Chloro-2-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester. LC/MS [M+H].sup.+: 270.2
Step-4:
6-Chloro-2-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester
[0982] To a stirred solution of
6-Chloro-2-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester (1.50 g, 5.7 mmol) in THF was added borane methyl
sulfide (0.8 ml, 8.4 mmol) at 0.degree. C. and then stirred at room
temperature overnight. Methanol was added to the reaction mixture
and refluxed the solution for 1 hour. The methanolic solution was
concentrated and crude mass was purified by flash chromatography
(Si-gel, 5% ethlyl acetate-hexane) to afford 640 mg (43.9%) of
6-Chloro-2-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 6.71 (d, 1H), 6.55 (d, 1H), 6.50 (dd, 1H), 6.16 (bs, 1H),
4.06 (t, 2H), 3.57 (dd, 1H), 3.04 (d, 1H), 1.46 (s, 3H), 1.11 (t,
3H).
Step-5:
6-Chloro-2-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid
[0983] To a solution of
6-Chloro-2-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester (170 mg, 0.7 mmol) in THF: water (1:1) was added
LiOH (70 mg, 1.7 mmol) under ice cold condition and stirred at room
temperature for 2 hour. After completion of the reaction solvent
was evaporated, added water, acidified with 1(N) HCl solution at
0.degree. C. and extracted with ethyl acetate. The organic layer
was washed with water, brine and dried over Na.sub.2SO.sub.4.
Conecntration of organic layer afforded 100 mg (62.8%) of
6-Chloro-2-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid. LC/MS [M+H].sup.+: 228.2
Step-6:
1-(6-Chloro-2-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-
-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0984] To a stirred solution of
6-Chloro-2-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid (100 mg, 0.44 mmol) was taken in dry DMF (1 ml) and was added
EDCI (110 mg, 0.57 mmol), HOBT (30 mg, 0.22 mmol) and DIPEA (0.2
ml, 1.1 mmol) at 0.degree. C. The reaction mixture was stirred at
room temperature for 30 mins and
4-(4-fluoro-benzyl)-piperidine-4-carbonitrile (125 mg, 0.57 mmol)
was added at 0.degree. C. The reaction mixture was stirred at room
temperature overnight and was added crushed ice, stirred, extracted
with ethyl acetate. The organic layer was washed with water, brine
and dried over Na.sub.2SO.sub.4. The organic layer was concentrated
under reduced pressure and obtained crude mass was purified by
flash chromatography (Si-gel, 20% ethyl acetate- hexane) to afford
80 mg (42.5%) of
1-(6-Chloro-2-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+: 428.2.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.32 (m, 2H),
7.17 (t, 2H), 6.76 (d, 1H), 6.55 (d, 1H), 6.47 (d, 1H), 6.24 (bs,
1H), 4.50 (m, 5H), 3.67 (m, 1H), 2.94 (m, 4H), 1.79 (m, 2H), 1.46
(s, 3H). HPLC: 95.1%
Example 141
1-(6-Chloro-7-dimethylamino-2-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-ca-
rbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00177## ##STR00178##
[0985]
6-Chloro-2-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester was prepared by a process as described in example
140. Step-1:
6-Chloro-2-methyl-7-nitro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
oxylic acid ethyl ester
[0986] To a solution of
6-Chloro-2-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester (500 mg, 1.96 mmol) in concentrated
H.sub.2SO.sub.4 (5 ml), NaNO.sub.3 (166 mg, 1.96 mmol) was added
portion wise at -15 to -20.degree. C. Stirring was continued at
this temperature for 1 hour. UV Intensity of the new spot generated
was increased slightly after stirring of this reaction mass at
-10.degree. C. for half an hour and then no improvement was
observed after stirring at -5.degree. C. for another half an hour.
This reaction mass was then poured into crushed ice and stirred
well. The crude mass was extracted with ethyl acetate, washed with
water, brine and dried over Na.sub.2SO.sub.4. The organic layer was
concentrated and crude mass was purified by flash chromatography
(Si-gel, 10% ethyl acetate-hexane) to get 240 mg (40.7%) of
6-Chloro-2-methyl-7-nitro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.55 (m, 2H), 6.73 (s, 1H), 4.09 (m, 2H), 3.75 (dd, 1H),
3.22 (m, 1H), 1.53 (s, 3H), 1.11 (t, 3H).
Step-2:
6-Chloro-2-methyl-7-nitro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicar-
boxylic acid 4-tert-butyl ester 2-ethyl ester
[0987] To a solution of
6-Chloro-2-methyl-7-nitro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester (240 mg, 0.8 mmol) in THF (10 ml), catalytic
amount of DMAP and (BOC).sub.2O (0.2 ml, 0.8 mmol) was added at
0.degree. C. The reaction mass was stirred under cold condition for
2.5 hour. The reaction mass was concentrated, added ethyl acetate.
The organic part was washed with water, brine, dried over
Na.sub.2SO.sub.4 and then concentrated to get 290 mg (90.4%) of
6-Chloro-2-methyl-7-nitro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester. LC/MS [M+H].sup.+:
400.0.
Step-3:
7-Amino-6-chloro-2-methyl-2,3-dihydro-benzo[1,4]oxazine-2,4-dicar-
boxylic acid 4-tert-butyl ester 2-ethyl ester
[0988] To a solution of
6-Chloro-2-methyl-7-nitro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester (290 mg, 0.7 mmol) in
THF-H.sub.2O (4:1), Zn dust (331 mg, 5.1 mmol) and NH4Cl (116 mg,
2.2 mmol) was added. The reaction mixture was refluxed for 5 hour.
The reaction mass was filtered over celite bed, added ethyl
acetate, washed with water, brine and dried over Na.sub.2SO.sub.4.
The organic layer was concentrated under reduced pressure to get
230 mg (88.6%) of
7-Amino-6-chloro-2-methyl-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester. LC/MS [M+H].sup.+:
371.4.
Step-4
[0989] To a solution of
7-Amino-6-chloro-2-methyl-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester (230 mg, 0.62 mmol) in dry
THF added dry K.sub.2CO.sub.3 (214 mg, 1.6 mmol) and CH.sub.3I
(0.12 ml, 1.9 mmol) at 0.degree. C. and then heated at 50.degree.
C. for 3 hour. The reaction mass was diluted with water, extracted
with ethyl acetate, washed with water, brine and dried over
Na.sub.2SO.sub.4. The organic layer was concentrated under reduced
pressure and crude mass (210 mg) contains both the
6-Chloro-2-methyl-7-methylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarbo-
xylic acid 4-tert-butyl ester 2-ethyl ester and
6-Chloro-7-dimethylamino-2-methyl-2,3-dihydro-benzo[1,4]oxazine-2,4-dicar-
boxylic acid 4-tert-butyl ester 2-ethyl ester . LC/MS [M+H].sup.+:
399.2,385.4.
Step-5
[0990] To a crude mixture of step 4 (210 mg, 0.53 mmol) in THF-H2O
(3:1) was added LiOH (55 mg, 1.3 mmol) at 0.degree. C. and stirred
at room temperature for 2 hour. The reaction mixture was
concentrated, diluted with water, extracted with ethyl acetate,
washed with water, brine and dried over Na.sub.2SO.sub.4. The
organic layer was concentrated under reduced pressure afforded 180
mg of a mixture of
6-Chloro-2-methyl-7-methylamino-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarbo-
xylic acid 4-tert-butyl ester and
6-Chloro-7-dimethylamino-2-methyl-2,3-dihydro-benzo[1,4]oxazine-2,4-dicar-
boxylic acid 4-tert-butyl ester. LC/MS [M+H].sup.+: 371.2 and
357.2.
Step-6
[0991] To a crude mixture of step-5 product (180 mg, 0.5 mmol) in
dry DMF (2 ml) was added EDCI (125 mg, 0.65 mmol), HOBT (34 mg,
0.25 mmol) and DIPEA (0.25 ml, 1.5 mmol) at 0.degree. C. The
reaction mixture stirred at room temperature for 30 mins and was
added 4-(4-Fluoro-benzyl)-piperidine-4-carbonitrile (106 mg, 0.5
mmol) at 0.degree. C. The reaction mixture was stirred at room
temperature overnight and added crushed ice, stirred, extracted
with ethyl acetate, washed with water, brine and dried over
Na.sub.2SO.sub.4. The organic layer was concentrated under reduced
pressure and crude mass was purified by flash chromatography (10%
ethyl acetate-hexane) to get 145 mg (50.8%) mixture of coupled
product
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2-methyl-7-
-methylamino-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester and
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]--
7-dimethylamino-2-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester. LC/MS [M+H].sup.+: 571.2 and 557.4.
Step-7:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7--
dimethylamino-2-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid tert-butyl ester
[0992] To a solution of a mixture of product of step-6 (145 mg,
0.26 mmol) in THF was added dry K.sub.2CO.sub.3 (54 mg, 1.6 mmol)
and CH.sub.3I (0.01 ml, 0.13 mmol) at 0.degree. C. and heated at
50.degree. C. overnight. The reaction mass was diluted with water,
extracted with ethyl acetate, washed with water, brine and dried
over Na.sub.2SO.sub.4. The organic layer was concentrated under
reduced pressure to afford 135 mg (90.9%) of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-dimethyl-
amino-2-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester. LC/MS [M+H].sup.+: 571.4.
Step-8:
1-(6-Chloro-7-dimethylamino-2-methyl-3,4-dihydro-2H-benzo[1,4]oxa-
zine-2-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0993] To a stirred solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-dimethyl-
amino-2-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester (135 mg, 0.23 mmol) in DCM (10 ml) was added TFA
(0.18 ml, 2.4 mmol) at 0.degree. C. and stirred at room temperature
for 2 h. The reaction mixture was completely evaporated under
reduced pressure, added small amount of water, basified with 1(N)
NaOH solution, extracted with ethyl acetate, washed with water,
brine and dried over Na.sub.2SO.sub.4. The organic layer was
concentrated and crude mass was washed with hexane to afford 20 mg
(18.5%) of J
1-(6-Chloro-7-dimethylamino-2-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-c-
arbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS
[M+H].sup.+: 471.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.32 (bs, 2H), 7.17 (m, 2H), 6.66 (s, 1H), 6.59 (s, 1H), 5.8
1(bs, 1H), 4.60 (m, 4H), 3.62 (d, 1H), 2.90 (m, 3H), 2.56 (s, 6H),
1.81 (m, 2H), 1.46 (s,3H). HPLC: 93.5%.
Example 142
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-dimethyla-
mino-2,3-dihydro-benzo[1,4]oxazine-4-carbonitrile
##STR00179##
[0995]
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-di-
methylamino-2,3-dihydro-benzo[1,4]oxazine-4-carbonitrile was
prepared by a process as described in example 76.
Step-1:
1-[6-Chloro-7-dimethylamino-4-(2H-tetrazol-5-yl)-3,4-dihydro-2H-b-
enzo[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[0996] To the stirred solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-dimethyl-
amino-2,3-dihydro-benzo[1,4]oxazine-4-carbonitrile (300 mg, 0.62
mmol) in DMF were added NH.sub.4Cl (134 mg, 2.5 mmol) and NaN.sub.3
(162 mg, 2.5 mmol). The reaction mixture was heated overnight at
120.degree. C. The reaction mixture was diluted with ethyl acetate,
washed with water, brine and dried over Na.sub.2SO.sub.4. The
organic layer was concentrated under reduced pressure and crude
mass was purified by flash chromatography (Si-gel, 2.0% MeOH-DCM)
to afford 25 mg (7.7%) of
1-[6-Chloro-7-dimethylamino-4-(2H-tetrazol-5-yl)-3,4-dihydro-2H-benzo[1,4-
]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile.
LC/MS [M+H].sup.+: 525.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 8.0-6.7 (m, 7H), 5.35-2.93 (m, 10H), 2.67 (s, 6H),
1.98-1.52 (m, 3H). LCMS purity: 90.3%.
Example 143
1-[6-Chloro-7-(2-methoxy-phenyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbon-
yl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00180##
[0997]
1-[6-Chloro-7-(2-methoxy-phenyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-
-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was
prepared by a process similar to that described in example 128.
LC/MS [M+H].sup.+: 509.4. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 7.32 (m, 3H), 7.17 (m, 2H), 7.06 (m, 2H), 6.96 (m,
1H), 6.67 (bs, 1H), 6.60 (bs, 1H), 6.18(bs, 1H), 4.96 (bs, 1H),
4.39 (m, 1H), 4.11 (m, 1H), 3.70 (s, 3H), 3.43 (m, 1H), 3.14 (m,
1H), 2.92 (m, 2H), 2.69 (m, 1H), 1.98 (s, 1H), 1.73 (m, 3H), 1.54
(m, 1H).
[0998] HPLC: 90.3%.
Example 144
1-(6-Chloro-7-pyridin-2-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4--
(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00181##
[0999] Step 1:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-pyridin--
2-yl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester
[1000] A solution of
7-Bromo-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,-
3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (250
mg, 0.42 mmol),
2-[4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (112 mg,
0.54 mmol), Na.sub.2CO.sub.3 (90 mg, 0.84 mmol) in toluene-water
was degassed for 1 hour and was added [Pd (dppf).sub.2Cl.sub.2] was
added at argon atmosphere. The reaction mixture was heated at
90.degree. C. for overnight and diluted with water. The organics
was extracted with ethyl acetate. The organic layer was washed with
water, brine and dried over Na.sub.2SO.sub.4. The volatile
components were removed under reduced pressure and purified by
column chromatography (Si-gel, 30% ethyl acetate- hexane) to afford
35 mg (14%) of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-pyridin--
2-yl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester. LC/MS [M+H].sup.+: 591.2.
Step 2:
1-(6-Chloro-7-pyridin-2-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-car-
bonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[1001] To a solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7-pyridin--
2-yl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester (35 mg, 0.06 mmol) in DCM was added TFA (0.5 ml) and stirred
at RT for 1 hours. The volatile components were removed under
reduced pressure and residue was diluted with water. It was
basified and extracted with ethyl acetate. The organic layer was
washed with water, brine and dried over Na.sub.2SO.sub.4. The
organic layer was concentrated and washed with hexane to afford 15
mg (51.6%) of
1-[6-Chloro-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-
-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS
[M+H].sup.+: 491.0. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 8.61 (bs, 1H), 7.81 (m, 1H), 7.62 (m, 1H), 7.33 (bs, 3H),
7.18 (bs, 2H), 6.99 (s, 1H), 6.71 (s, 1H), 6.44 (s, 1H), 5.00 (m,
1H), 4.60 (m, 1H), 4.12 (m, 1H), 3.42(m, 1H), 2.95 (s, 2H), 2.68(m,
1H), 1.79 (m, 3H), 1.54 (m, 1H), 1.23 (m, 1H), 0.85 (m, 1H). HPLC:
85.4%.
Example 145
1-(7-Acetyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-flu-
oro-benzyl)-piperidine-4-carbonitrile
##STR00182## ##STR00183##
[1002] Step-1:
4-Benzyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester
[1003] To a solution of
6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid ethyl
ester (1.8 g, 7.45 mmol) in acetonitrile were added K.sub.2CO.sub.3
(2.2 g, 15.64 mmol) and Benzyl bromide (1.0 ml, 8.19 mmol). The
reaction mixture was refluxed overnight, concentrated and extracted
with ethyl acetate. The organic layer was washed with water, brine
and dried over Na.sub.2SO.sub.4. It was concentrated and purified
by column chromatography (Silica gel, 4% ethyl acetate-hexane) to
afford 1.48 g (59.9%) of
4-Benzyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.34 (m, 2H), 7.25 (m, 3H), 6.80 (m, 1H), 6.66 (m, 1H), 6.60
(m, 1H), 5.09 (bs, 1H), 4.52 (m, 1H), 4.38 (m, 1H), 4.09 (m, 2H),
3.55 (m, 2H), 1.13(m, 3H).
Step-2:
4-Benzyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid
[1004] To a solution of
4-Benzyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester (1 g, 3.0 mmol) in (4:1) THF:H.sub.2O was added
LiOH (252 mg, 6.0 mmol) at cold condition. The reaction mixture was
stirred at RT for 2 hours. It was concentrated, diluted with water
and acidified with aq. HCl in cold condition. It was extracted with
ethyl acetate and organic layer was washed with water, brine and
dried over Na.sub.2SO.sub.4. The organic layer was concentrated to
afford 950 mg (crude) of
4-Benzyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 13.17
(hump, 1H), 7.33 (m, 2H), 7.28 (m, 3H), 6.78 (m, 1H), 6.58 (m, 2H),
4.96 (s, 1H), 4.47 (m, 2H), 3.53 (m, 2H).
Step-3:
1-(4-Benzyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-
-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[1005] To a solution of
4-Benzyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid (950 mg, 3.13 mmol) in DMF was added DIPEA (1.7 ml, 9.38 mmol)
drop wise at cold condition. EDCI (900 mg, 4.69 mmol), HOBT (506
mg, 3.75 mmol) were then added to the reaction mixture and stirred
for 0.5 hour. 4-(4-Fluoro-benzyl)-piperidine-4-carbonitrile (683
mg, 3.13 mmol) was added to the reaction mixture and stirred
overnight at RT. It was diluted with water and extracted with ethyl
acetate. Organic layer was washed with water, brine and dried over
Na.sub.2SO.sub.4. It was concentrated and purified by column
chromatography (Silica gel, 20% ethyl acetate-hexane) to afford 1.2
g (76%) of
1-(4-Benzyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
504.2.
Step-4:
1-(4-Benzyl-6-chloro-7-formyl-3,4-dihydro-2H-benzo[1,4]oxazine-2--
carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[1006] POCl.sub.3 (0.5 ml, 5.34 mmol) was added drop wise to DMF (3
ml) at ice-cold condition and stirred for 0.5 hour.
1-(4-Benzyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile (900 mg, 1.78 mmol) was then
added to the DMF-POCl.sub.3 and heated at 60.degree. C. overnight.
The reaction mixture was quenched with ice-water and extracted with
ethyl acetate. The organic layer was dried over Na.sub.2SO.sub.4
and concentrated under reduced pressure to afford 770 mg (81.3%)
1-(4-Benzyl-6-chloro-7-formyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl-
)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. (ppm): 10.0 (m, 1H), 7.29 (m, 7H), 7.19
(m, 3H), 6.78 (s, 1H), 5.25 (bs, 1H), 4.75 (m, 1H), 4.64 (m, 1H),
4.35 (m, 1H), 4.05(m, 1H), 3.61 (s, 2H), 2.95 (m, 3H), 2.70 (m,
1H), 1.80 (m, 3H), 1.53 (m, 1H).
Step-5:
1-[4-Benzyl-6-chloro-7-(1-hydroxy-ethyl)-3,4-dihydro-2H-benzo[1,4-
]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[1007] To a solution of
1-(4-Benzyl-6-chloro-7-formyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl-
)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile (200 mg, 0.38 mmol)
in THF was added [3(M) MeMgBr] (0.15 ml, 0.41 mmol) drop wise at
-78.degree. C. The reaction mixture was stirred overnight at RT,
quenched with saturated aq. NH.sub.4Cl solution and extracted with
ethyl acetate. The organic layer was washed with water, brine and
dried over Na.sub.2SO.sub.4. The organic solution was concentrated
and purified by column chromatography (Silica gel, 30% ethyl
acetate-hexane) to afford 138 mg (68%) of
1-[4-Benzyl-6-chloro-7-(1-hydroxy-ethyl)-3,4-dihydro-2H-benzo[1,4]oxazine-
-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS
[M+H].sup.+: 548.6.
Step-6:
1-(7-Acetyl-4-benzyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2--
carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[1008] To a solution of
1-[4-Benzyl-6-chloro-7-(1-hydroxy-ethyl)-3,4-dihydro-2H-benzo[1,4]oxazine-
-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile (300 mg,
0.55 mmol) in ethyl acetate was added IBX (307 mg, 1.09 mmol) at
cold condition and heated at 50.degree. C. overnight. The
precipitated solid was filtered off and mother liquor was
concentrated. The crude organics was purified by column
chromatography (Silica gel, 30% ethyl acetate-hexane) to afford 130
mg (43.3%) of
1-(7-Acetyl-4-benzyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl-
)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+:
546.6.
Step-7:
1-(7-Acetyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-
-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[1009] To a solution of
1-(7-Acetyl-4-benzyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl-
)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile (130 mg, 0.24 mmol)
in HPLC ethyl acetate was added 10% Pd--C. The reaction mixture was
hydrogenated at 50 psi for 5 hours. The catalyst was filtered off
and mother liquor was concentrated. The crude organics was purified
by column chromatography (Silica gel, 40% ethyl acetate-hexane) to
afford 15 mg (13.7%) of
1-(7-Acetyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+: 456.2.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.61-6.62 (m,
7H), 5.00 (m, 1H), 4.37 (m, 1H), 4.10 (m, 1H), 2.96 (m, 3H), 2.66
(m, 1H), 1.90 (m, 1H), 1.72 (m, 4H), 1.53 (m, 2H), 1.24 (m, 2H).
HPLC: 91.9%
Example 146
1-(6-Chloro-7-oxazol-5-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(-
4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00184##
[1010]
4-Benzyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester was prepared by a process as described in example
144. Step-1:
1-(4-Benzyl-6-chloro-7-oxazol-5-yl-3,4-dihydro-2H-benzo[1,4]oxazi-
ne-2-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[1011] To a mixture of
1-(6-Chloro-7-formyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fl-
uoro-benzyl)-piperidine-4-carbonitrile (1 g, 1.87 mmol) and sodium
methoxe (305 mg, 5.6 mmol) in methanol was added
p-Tosylmethylisocyanide (441 mg, 2.26 mmol). The reaction mixture
was refluxed one hour. The reaction mixture was concentrated,
diluted with water and extracted with ethyl acetate. The organic
layer was concentrated to afford 461 mg (43%) of
1-(4-Benzyl-6-chloro-7-oxazol-5-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-car-
bonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS
[M+H].sup.+: 571.0.
Step-2:
1-(6-Chloro-7-oxazol-5-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carb-
onyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[1012] To a solution of
1-(4-Benzyl-6-chloro-7-oxazol-5-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-car-
bonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile (200 mg, 0.35
mmol) in HPLC ethyl acetate was added 10% Pd--C. The reaction
mixture was hydrogenated at 50 psi for 5 hours. The catalyst was
filtered off and mother liquor was concentrated. The crude organics
was purified by column chromatography (Silica gel, 45% ethyl
acetate-hexane) to afford 17 mg (10%) of
1-(6-Chloro-7-oxazol-5-yl-3,4-dihydro-2H-benzo[1,4]oxazine-2-car-
bonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS
[M+H].sup.+: 481.6. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 8.41 (m, 1H), 7.49 (bs, 1H), 7.34 (bs, 2H), 7.19 (t, 2H)
7.08 (m, 1H), 6.74 (s 1H), 6.59 (bs 1H), 5.03 (bs 1H), 4.38 (m,
1H), 4.11 (m, 1H), 3.43-2.67 (m, 6H), 1.89-1.54 (m, 4H). HPLC:
88.5%.
Example 147
1-(4-Chloro-2-methyl-3,6,7,8-tetrahydro-9-oxa-1,3,6-triaza-cyclopenta[a]na-
phthalene-8-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00185##
[1013]
6-Chloro-7,8-dinitro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester was prepared by a process similar to that
described above in example 51. Step-1:
6-Chloro-7,8-dinitro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester
[1014] To a solution of
6-Chloro-7,8-dinitro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid ethyl ester (3 g, 9.05 mmol) in THF (40 ml) was added DMAP
(111 mg, 0.91 mmol) and di-tert-butyl dicarbonate (4.6 ml, 21.07
mmol) drop wise at room temperature. The reaction mixture was
stirred at room temperature for 5 h and concentrated under reduced
pressure. The crude mass was purified by column chromatography
(Si-gel, 5% ethyl acetate-hexane) to afford 1.29 g (33%) of
6-Chloro-7,8-dinitro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester. LC/MS [M+NH.sub.3].sup.+:
449.2.
Step-2:
6-Chloro-7,8-dinitro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxyl-
ic acid 4-tert-butyl ester
[1015] To a stirred suspension of
6-Chloro-7,8-dinitro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-ethyl ester (1.29 g, 2.99 mmol) in
THF-H.sub.2O (3:1), LiOH (313 mg, 7.47 mmol) was added portion wise
under cold condition and stirred at room temperature for 2 hour.
The reaction mixture was concentrated under reduced pressure,
diluted with water. The solution was acidified with 50% acetic acid
solution under cold condition. The organic mass was extracted with
ethyl acetate, washed with water and brine. The organic layer was
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The crude mass was then tripped with toluene thrice to
get 1.16 g (96%) of
6-Chloro-7,8-dinitro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 8.15 (s, 1H), 5.31 (s, 1H), 4.54 (d,1H), 3.66
(d,1H), 1.38 (s, 9H).
Step-3:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7,-
8-dinitro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
tert-butyl ester
[1016] To a stirred solution of
6-Chloro-7,8-dinitro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic
acid 4-tert-butyl ester (1.16 g, 2.87 mmol) in DMF (5.0 ml) was
added EDCI (715 mg, 3.73 mmol), HOBT (194 mg, 1.44 mmol) &
DIPEA (1.5 ml, 8.61 mmol) at 0.degree. C. and stirred at room
temperature for 30 minutes.
4-(4-Fluoro-benzyl)-piperidine-4-carbonitrile (627 mg, 2.87 mmol)
was added at 0.degree. C. to the previous solution and stirred at
room temperature overnight. The reaction mixture was quenched with
crushed ice, stirred, extracted with ethyl acetate. The organic
layer was washed with water and brine solution. The organic layer
was dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The crude mass was purified by column chromatography
(Si-gel, 25% ethyl acetate-hexane) to afford 900 mg (51.9%) of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7,8-dinitr-
o-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester.
LC/MS [M+NH.sub.3].sup.+: 621.6.
Step-4: 7,
8-Diamino-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]--
2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tent-butyl
ester
[1017] To a stirred suspension of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-7,8-dinitr-
o-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
G (900 mg, 1.49 mmol) in 25 ml MeOH--H.sub.2O (4:1), Zn-dust (1.95
g, 29.8 mmol) and NH.sub.4Cl (797 mg, 14.9 mmol) was added at
0.degree. C. The reaction mass was stirred at room temperature
overnight. The reaction mass was filtered over a celite bed and
concentrated. To that added water, extracted with ethyl acetate,
washed with water, brine, dried with Na.sub.2SO.sub.4 and
concentrated to get 600 mg (74%) of
7,8-Diamino-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl-
]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester.
LC/MS [M+H].sup.+: 544.0.
Step-5:
1-(4-Chloro-2-methyl-3,6,7,8-tetrahydro-9-oxa-1,3,6-triaza-cyclop-
enta[a]naphthalene-8-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitri-
le
[1018] To a stirred solution of
7,8-Diamino-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl-
]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
(100 mg, 0.18 mmol) in acetic anhydride (1.5 ml) was added 5(M) HCl
(0.5 ml) and heated at 80.degree. C. for 2 hours. The reaction
mixture was concentrated, basified with saturated NaHCO.sub.3
solution and extracted with ethyl acetate. The organic layer was
washed with water, brine, dried with Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The crude mass was purified by
column chromatography (Si-gel, 1.8% MeOH-DCM) to get 25 mg (29.7%)
of
1-(4-Chloro-2-methyl-3,6,7,8-tetrahydro-9-oxa-1,3,6-triaza-cyclopenta[a]n-
aphthalene-8-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile.
LC/MS [M+H].sup.+: 468.6. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 7.35 (m, 2H), 7.20 (m, 2H), 6.31 (m, 1H), 5.40 (m,
1H), 4.92 (m, 2H), 4.42 (m, 2H), 4.25 (m, 2H), 3.20 (m, 1H), 2.97
(d, 2H), 2.76 (m, 1H), 2.45 (s, 3H), 1.80 (m, 2H), 1.53 (m, 1H).
HPLC: 94.36%.
Example 148
1-(4-Chloro-3,6,7,8-tetrahydro-9-oxa-1,3,6triazacyclopenta[a]naphthalene-8-
-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00186##
[1019]
7,8-Diamino-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-ca-
rbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl
ester was prepared by a process as described in example 145.
Step-1:
1-(4-Chloro-3,6,7,8-tetrahydro-9-oxa-1,3,6triazacyclopenta[a]naphthalene--
8-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[1020] To a stirred solution of
7,8-Diamino-6-chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl-
]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester
(95 mg, 0.17 mmol) in formic acid was added 5(M) HCl (0.5 ml) and
heated at 80.degree. C. for 2 hours. The reaction mixture was
concentrated, basified with saturated NaHCO.sub.3 solution and
extracted with ethyl acetate. The organic layer was washed with
water, brine, dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The crude mass was purified by column
chromatography (Si-gel, 2% MeOH-DCM) to get 15 mg (19.4%) of
1-(4-Chloro-3,6,7,8-tetrahydro-9-oxa-1,3,6-triazacyclopenta[a]naphthalene-
-8-carbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS
[M+H].sup.+: 454.2. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 8.04 (s, 1H), 7.35 (m, 2H), 7.21 (m, 2H), 6.38 (m, 1H), 5.40
(m, 1H), 5.03 (m, 2H), 4.54 (m, 1H), 4.42 (m, 2H), 4.20 (m, 1H),
3.19 (m, 2H), 2.95 (m, 2H), 2.76 (m, 1H), 1.80 (m, 2H). HPLC:
93.9%.
Example 149
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dihydro-
-2H-benzo[1,4]oxazine-7-carboxylic acid methylamide
##STR00187##
[1021] Step-1:
6-Chloro-7-iodo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
ethyl ester
[1022] To a stirred solution of
6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid ethyl
ester (5 g, 20.68 mmol) in acetic acid was added iodine (5.26 g,
20.68 mmol) drop wise at 10.degree. C. The reaction mixture was
stirred for 30 min at same temperature. The reaction mixture was
poured in ice-water, extracted the compound with ethyl acetate,
washed with water, brine, dried over Na.sub.2SO4 and concentrated
under reduced pressure. Thus obtained crude was purified through
repeated column chromatography (Si-gel, 20% DCM-Hex) to afford 1.1
g (14.5%) of
6-Chloro-7-iodo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
ethyl ester . LC/MS [M+H].sup.+: 368.2.
Step-2:
6-Chloro-7-iodo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid
[1023] To a stirred solution of
6-Chloro-7-iodo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
ethyl ester (400 mg, 1.09 mmol) in THF: Water (3:1) was added LiOH
(46 mg, 1.09 mmol) and stirred the reaction mixture for 2 h at room
temperature. The reaction mixture was concentrated, diluted with
water, acidified with dilute acetic acid and extracted the organics
with ethyl acetate. The organic layer was washed with water, brine,
dried over Na.sub.2SO4 and concentrated under reduced pressure.
Washed the crude with hexane to afford 260 mg (70.3%) of
6-Chloro-7-iodo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid.
The material was used in forward reaction without any
characterization.
Step-3:
1-(6-Chloro-7-iodo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-
-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[1024] To a solution of
6-Chloro-7-iodo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid
(260 mg, 0.77 mmol) in DMF was added
4-(4-Fluoro-benzyl)-piperidine-4-carbonitrile (168 mg, 0.77 mmol),
EDCI (220 mg, 1.15 m.mol), HOBt (125 mg, 0.92 m.mol) and DIPEA (297
mg, 2.23 m.mol) at 5-10.degree. C. The reaction mixture was stirred
at room temperature for 15 hours, diluted with water and extracted
with ethyl acetate. The organic layer was washed with water, brine
and dried over Na.sub.2SO.sub.4. The organic layer was concentrated
and purified over column chromatography (Si-gel, 30% ethyl
acetate-hexane) to afford 390 mg (93.8%) of
1-(6-Chloro-7-iodo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fluo-
ro-benzyl)-piperidine-4-carbonitrile. LC/MS [M+H].sup.+: 540.2.
Step-4:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,-
4-dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid methyl ester
[1025] A solution of
1-(6-Chloro-7-iodo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fluo-
ro-benzyl)-piperidine-4-carbonitrile (100 mg, 0.19 mmol) in
triethylamine-methanol (1:1) was degassed with argon during 30
mins. To the degassed solution were added Pd(OAc)2 (4 mg, 0.019
mmol) and Bis-1,3-(diphenylphosphino) propane (DPP) (15 mg, 0.037
mmol) in argon atmosphere. The reaction mixture was heated at
70.degree. C. in presence of 220 psi carbon monoxide in a autoclave
for overnight. The reaction mixture was cooled and filtered through
celite bed. The methanolic solution was concentrated and purified
through column chromatography (Si-gel, 40% ethyl acetate-hexane) to
afford 33 mg (36.8%) of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dihydr-
o-2H-benzo[1,4]oxazine-7-carboxylic acid methyl ester. LC/MS
[M+H].sup.+: 540.4.
Step-5:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,-
4-dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid methylamide
[1026] To a solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dihydr-
o-2H-benzo[1,4]oxazine-7-carboxylic acid methyl ester (24 mg, 0.042
mmol) was dissolved in excess methylamine solution in THF and was
heated at 90.degree. C. in a sealed tube overnight. The reaction
mixture was cooled and concentrated. The crude mass was purified
through column chromatography (Si-gel, 2% MeoH-DCM) to afford 9 mg
(45.6%) of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dihydr-
o-2H-benzo[1,4]oxazine-7-carboxylic acid methylamide. LC/MS
[M+H].sup.+: 471.0. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.95 (m, 1H), 7.34 (m, 2H), 7.19 (m, 2H), 6.83 (m, 1H), 6.59
(s, 1H), 6.46 (bs, 1H), 4.95 (m, 1H), 4.38 (m, 1H), 4.06 (m, 1H),
3.43 (m, 1H), 3.16 (m, 1H), 3.00 (bs, 2H), 2.69 (bs, 3H), 1.89-1.53
(m, 5H). HPLC: 93.0%.
Example 150
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dihydro-
-2H-benzo[1,4]oxazine-7-carbonitrile
##STR00188##
[1027]
1-(6-Chloro-7-iodo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(-
4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared by a
process as described in example 149.
[1028] One drop of water was added to DMAC (1.5 ml) and degassed
with argon for 1 hour orior to adding reactant.
1-(6-Chloro-7-iodo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonyl)-4-(4-fluo-
ro-benzyl)-piperidine-4-carbonitrile (100 mg, 0.18 mmol) was
dissolved in DMAC at room temperature. To this solution was added
Zn(CN).sub.2 (34 mg, 0.29 mmol), Pd.sub.2(dba).sub.3 (8 mg, 0.009
mmol), dppf (9 mg, 0.067 mmol). The resulting mixture was heated at
120.degree. C. overnight. The reaction mixture was diluted with
water, extracted with ethyl acetate, washed with water, brine. The
organic layer was dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure. The crude mass was purified by column
chromatography (silica gel, 0.5% MeOH-DCM) to get 28 mg (34.4%)
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dihydr-
o-2H-benzo[1,4]oxazine-7-carbonitrile. LC/MS [M+H].sup.+: 439.6.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.24 (m, 6H),
6.73 (s, 1H), 5.03 (m, 1H), 4.36 (m, 1H), 4.07 (m, 1H), 3.51 (m,
1H), 3.31 (m, 1H), 3.15 (m, 2H), 2.95 (m, 2H), 2.67 (m, 1H), 1.80
(m, 3H). HPLC: 90.41%.
Example 151
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dihydro-
-2H-benzo[1,4]oxazine-7-carboxylic acid dimethylamide
##STR00189##
[1029]
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4--
dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid methyl ester was
prepared by a process as described in example 149.
[1030]
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,3--
dihydro-benzo[1,4]oxazine-4,7-dicarboxylic acid 4-tert-butyl ester
was prepared from
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dihydr-
o-2H-benzo[1,4]oxazine-7-carboxylic acid methyl ester by hydrolysis
with LiOH.
Step-1:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,-
4-dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid dimethylamide
[1031] To a suspension of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,3-dihydr-
o-benzo[1,4]oxazine-4,7-dicarboxylic acid 4-tert-butyl ester (200
mg, 0.36 mmol) in dichloromethane was added thionyl chloride (2 ml)
and hetaed at 50.degree. C. The reaction mixture was concentrated
under reduced pressure and tripped twice with toluene. The crude
mass was stirred at room temperature with dimethylamine solution in
THF (3 ml). The reaction mixture was concentrated and purified the
crude mass through column chromatography (Si-gel, 2% MeOh-DCM) to
afford 35 mg (16.7%) of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dihydr-
o-2H-benzo[1,4]oxazine-7-carboxylic acid dimethylamide. LC/MS
[M+H].sup.+: 585.2.
Step-2:
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,-
4-dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid dimethylamide
[1032] To a solution of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dihydr-
o-2H-benzo[1,4]oxazine-7-carboxylic acid dimethylamide (35 mg, 0.06
mmol)in DCM was added trifluoroacetic acid (2 ml). The reaction
mixture was stirred for about 12 h. The reaction mixture was
concentrated and washed with dry ether. The resulting TFA salt was
diluted with a minimum volume of water and neutralized with aq.
NaOH solution at 5-10.degree. C. Extraction of the neutralized
solution with ethyl acetate, washed with water and brine solution.
The organic layer was dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure. The crude was purified through column
chromatography (Si-gel, 2% MeOH-DCM) to afford 9 mg (30.9%) of
6-Chloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-3,4-dihydr-
o-2H-benzo[1,4]oxazine-7-carboxylic acid dimethylamide. LC/MS
[M-H].sup.+: 483.5. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.33 (m, 2H), 7.19 (m, 2H), 6.65 (bs, 1H), 6.62 (bs, 1H),
6.38 (m, 1H), 5.44 (m, 1H), 4.38 (m, 1H), 4.09 (m, 1H), 3.43 (m,
1H), 3.08 (m, 2H), 2.94 (s, 6H), 2.66 (s, 2H), 1.90-0.83 (m, 5H).
HPLC: 95.1%.
Example 152
1-[6-Chloro-7-(2-methyl-thiazol-4-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-c-
arbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
##STR00190##
[1033]
1-(7-Acetyl-4-benzyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-ca-
rbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile was prepared
by a process as described in example 145. Step-1 :
1-[4-Benzyl-7-(2-bromo-acetyl)-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine--
2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[1034]
1-(7-Acetyl-4-benzyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine-2-ca-
rbonyl)-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile (200 mg, 0.37
mol) in CHCl3 (5 mL) was added to a solution of CuBr2 (200 mg, 0.88
mmol) in EtOAc (5 mL). The mixture was stirred for 12 h at reflux
and then cooled to rt and filtered through Celite. The reaction
mixture was concentrated. Purification by column chromatography
(Si-gel, 40% ethyl acetate-hexane) gave 100 mg (43%) of
1-[4-Benzyl-7-(2-bromo-acetyl)-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine--
2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile. LC/MS
[M+H].sup.+: 62.6.2.
Step-2:
1-[4-Benzyl-6-chloro-7-(2-methyl-thiazol-4-yl)-3,4-dihydro-2H-ben-
zo[1,4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[1035] To a solution of
1-[4-Benzyl-7-(2-bromo-acetyl)-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine--
2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile (100 mg,
0.16 mmol) in ethanol was added thoacetamide (15 mg, 0.19 mmol) and
Na.sub.2CO.sub.3 (26 mg, 0.24 mmol). The reaction mixture was
refluxed for 6 h. The reaction mixture was concentrated, diluted
with water and extracted with ethyl acetate. The organic layer was
washed with water, brine and dried over Na.sub.2SO.sub.4. The
organic layer was concentrated under reduced pressure to afford 45
mg (46.8%) of
1-[4-Benzyl-6-chloro-7-(2-methyl-thiazol-4-yl)-3,4-dihydro-2H-benzo[1,4]o-
xazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile.
LC/MS [M+H].sup.+: 601.2.
Step-3:
1-[6-Chloro-7-(2-methyl-thiazol-4-yl)-3,4-dihydro-2H-benzo[1,4]ox-
azine-2-carbonyl]4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
[1036] To a solution of
1-[4-Benzyl-6-chloro-7-(2-methyl-thiazol-4-yl)-3,4-dihydro-2H-benzo[1,4]o-
xazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile
(22 mg, 0.037 mmol) in dichloroethane was added
1-chloroethylchloroformate (0.1 ml). The reaction mixture was
refluxed for 6 h and methanol (10 ml) was added. The reaction
mixture was refluxed again for another 3 h. The reaction mixture
was concentrated and purified through column chromatography
(Si-gel, 50% ethyl acetate-hexane) afford 6 mg (31.7%) of
1-[6-Chloro-7-(2-methyl-thiazol-4-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-2--
carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile.
[1037] LC/MS [M+H].sup.+: 511.2. HPLC: 87.2%.
Human CCR1 Binding Assay (Ki Determination in 96 Well Format)
Competition-Equilibrium Binding Assay
[1038] After trypsinization, CHO-K1-G.alpha.16 (CHO-K1 from ATCC,
G.alpha.16 cloned and expressed in CHO-K 1 cells in CBT) cells
expressing human wild-type CCR1 were harvested using calcium and
magnesium free HBSS (INVITROGEN) buffer and then resuspended at
400,000 cells/ mL in binding buffer (RPMI1640, pH 7.4, 0.2% BSA,
Complete protease inhibitor cocktail without EDTA from Roche)
Competition-binding assays were performed in 96 well plates
(Corning non binding surface flat clear bottom white 96 well),
using 25 .mu.L of cell suspension (10,000/well), 25 .mu.L/ well of
100 .mu.M solution of [125I]-RANTES (2200 Ci/mmol; Perkin Elmer
NEX292) as tracer for human CCR1 receptor, 25 .mu.L/ well of RPMI
buffer or various concentration of competitor/compound diluted in
RPMI and 25 .mu.L/ well of PVT-WGA SPA beads (GE) (0.1 mg/well).
Each well contained a final volume of 100 .mu.L with a final DMSO
concentration of 0.5%. The 96 well plates were incubated for 2
hours at room temperature in the dark without shaking. Bound
radioligand was counted with a beta scintillation counter (Wallac,
Micro-Beta Trilux counter) for 1 min per well. Total binding of
[125I]-RANTES was measured in the absence and presence of
competitor (compound), the nonspecific binding was measured with a
33-fold excess of BX471 (10 .mu.M final). In order to determine
binding parameters (Ki and IC.sub.50), the counts results were
analyzed using the one-site competition curve fitting functions in
GraphPad PRISM, v. 4.0 (San Diego, Calif.).
[1039] The compounds of the present invention typically exhibit
potency values of greater than 50% inhibition at 20 .mu.M in this
competitive binding assay.
[1040] The entire disclosures of all applications, patents and
publications, cited above and below, are hereby incorporated by
reference.
[1041] While the invention has been depicted and described by
reference to exemplary embodiments of the invention, such a
reference does not imply a limitation on the invention, and no such
limitation is to be inferred. The invention is capable of
considerable modification, alteration, and equivalents in form and
function, as will occur to those ordinarily skilled in the
pertinent arts having the benefit of this disclosure. The depicted
and described embodiments of the invention are exemplary only, and
are not exhaustive of the scope of the invention. Consequently, the
invention is intended to be limited only by the spirit and scope of
the appended claims, giving full cognizance to equivalence in all
respects.
* * * * *